Compositions and methods for preventing and treating conditions

ABSTRACT

Provided herein are compositions comprising a stable water-in-silicone emulsion, and methods and kits comprising the compositions for treating conditions.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/220,517, filed Dec. 14, 2018, which claims benefit of priority toU.S. Provisional Application No. 62/609,127, filed Dec. 21, 2017, andU.S. Provisional Application No. 62/607,286, filed Dec. 18, 2017, theentire contents of each of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to compositions, methods, and kits forvulvovaginal application and other conditions in a subject.

BACKGROUND

Various compositions are needed to provide lubricity and/or to protectskin and other tissue from damage and/or infection. Such compositionsare useful alone or with one or more active and/or bioactive agents,wherein the composition serves as a drug delivery vehicle (e.g., as atransdermal drug delivery vehicle).

In addition, vulvovaginal health continues to be an overlooked medicalneed, as most markets in this area are largely undifferentiated,especially with respect to over-the-counter or non-prescriptionproducts. For this reason, gynecological patients across alldemographics, from pre-menopause to post-menopause, who are sufferingfrom one or more vulvovaginal conditions are often treated withprescription products or regimens that typically have undesired productcharacteristics including, (1) insufficient efficacy duration from asingle application, (2) inadequate restoration of physiological stasis,(3) undesired side effects, and (4) untenable health risks.

Thus, there remains a need for a variety of compositions that providelubricity, protect skin and other tissue, and/or facilitate drugdelivery. In particular, there is a need for compositions andformulations capable of providing vulvovaginal symptom relief, treatingunderlying pathophysiology or infection of the vulvovaginal anatomy, orprophylactically protecting the vulvovaginal anatomy, with respect to anumber of vulvovaginal health conditions.

SUMMARY

Provided herein are, inter alia, compositions, formulations and methodsthat provide lubricity, protect skin, mucosa, and other tissues, andfacilitate drug delivery. Compositions, formulations and methods arealso provided for treating, preventing, and/or reducing the symptoms ofseverity of vulvovaginal and other conditions. Provided herein arevulvovaginal compositions designed to provide vulvovaginal symptomrelief, treat underlying pathophysiology or infection of thevulvovaginal anatomy, or prophylactically protect the vulvovaginalanatomy in a subject. In some embodiments, the vulvovaginal compositionscomprise a stable water-in-silicone emulsion, an emulsifier, a cellmembrane fluidity enhancing agent, a fatty acid, a preservative, and atleast one of, a bioactive agent, a pH buffering system, a viscosityenhancing agent, an antioxidant, a tocopherol, and an active agent. Inother embodiments, the vulvovaginal compositions consist of a stablewater-in-silicone emulsion, an emulsifier, a cell membrane fluidityenhancing agent, a fatty acid, a preservative, and at least one of, abioactive agent, a pH buffering system, a viscosity enhancing agent, anantioxidant, a tocopherol, and an active agent. In other embodiments,the vulvovaginal compositions consist essentially of a stablewater-in-silicone emulsion, an emulsifier, a cell membrane fluidityenhancing agent, a fatty acid, a preservative, and at least one of, abioactive agent, a pH buffering system, a viscosity enhancing agent, anantioxidant, a tocopherol, and an active agent.

Compositions, formulations and methods are also provided for treating orprotecting the skin. Provided herein are dermatological compositionsdesigned to provide treat or protect the skin in a subject. In someembodiments, the dermatological compositions comprise a stablewater-in-silicone emulsion, an emulsifier, a cell membrane fluidityenhancing agent, a fatty acid, a preservative, and at least one of, abioactive agent, a pH buffering system, a viscosity enhancing agent, anantioxidant, a tocopherol, a ceramide, and an active agent. In otherembodiments, the dermatological compositions consist of a stablewater-in-silicone emulsion, an emulsifier, a cell membrane fluidityenhancing agent, a fatty acid, a preservative, and at least one of, abioactive agent, a pH buffering system, a viscosity enhancing agent, anantioxidant, a tocopherol, a ceramide, and an active agent. In otherembodiments, the dermatological compositions consist essentially of astable water-in-silicone emulsion, an emulsifier, a cell membranefluidity enhancing agent, a fatty acid, a preservative, and at least oneof, a bioactive agent, a pH buffering system, a viscosity enhancingagent, an antioxidant, a tocopherol, a ceramide and an active agent.

Also provided herein are methods for preventing or treating a vaginalcondition in a subject, the method comprising administering to a subjecta composition comprising a stable water-in-silicone emulsion, whereinthe emulsion has a sterol at a concentration from about 0.1% to about 4%by weight of the total weight of the emulsion. In embodiments, thecomposition is administered into the vagina, onto and/or around thevulva, or any combination thereof.

In other examples, the methods described herein are used for preventingor treating a vaginal condition, including menopause, peri-menopause,post-menopause, vaginal dryness, dyspareunia, a bacterial infection, aviral infection, or a fungal infection.

In embodiments, the methods described herein provide a therapeuticallyeffective dose for up to 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12hours, 18 hours, 24 hours, 48 hours, 3 days, 5 days, 7 days, or 14 days.Furthermore, the methods comprise administering the composition every 1hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours,48 hours, 3 days, 5 days, 7 days, or 14 days.

Also provided herein are methods of preparing a water-in-siliconeemulsion comprising preparing an aqueous phase comprising water, a pHbuffering system, at least one active or bioactive agent, and apreservative, and separately preparing a silicone phase comprising asilicone oil, a silicone gum, and a sterol, a fatty acid, a tocopheroland a preservative, and adding the aqueous phase to the silicone phase,and mixing the combined phases until the water-in-silicone emulsion isformed, wherein the silicone phase comprises about 20-80% by weight ofthe composition, and the aqueous phase comprises about 20-80% by weightof the composition, based on the total weight of the composition. Inembodiments, the method further includes adding the aqueous phase to thesilicone phase under high shear mixing, e.g., where the high shearmixing utilizes a rotor-stator homogenizer.

Methods to provide vulvovaginal symptom relief, treat underlyingpathophysiology or infection of the vulvovaginal anatomy, orprophylactically protect the vulvovaginal anatomy in a subjectcomprising administering to said subject a vulvovaginal compositioncomprising, consisting of, or consisting essentially of a stablewater-in-silicone emulsion, an emulsifier, a cell membrane fluidityenhancing agent, a fatty acid, a preservative, and at least one of, abioactive agent, a pH buffering system, a viscosity enhancing agent, anantioxidant, a tocopherol, and an active agent, are also disclosedherein.

Methods to treat and protect the skin in a subject comprisingadministering to said subject a dermatological composition comprising,consisting of, or consisting essentially of a stable water-in-siliconeemulsion, an emulsifier, a cell membrane fluidity enhancing agent, afatty acid, a preservative, and at least one of, a bioactive agent, a pHbuffering system, a viscosity enhancing agent, an antioxidant, atocopherol, a ceramide, and an active agent, are also disclosed herein.

Further provided are kits for producing vulvovaginal compositions toprovide vulvovaginal symptom relief, treat underlying pathophysiology orinfection of the vulvovaginal anatomy, or prophylactically protect thevulvovaginal anatomy in a subject.

Further provided are kits for producing dermatological compositions totreat and protect the skin in a subject.

BRIEF DESCRIPTION OF THE DRAWINGS

This invention will be more fully understood from the following detaileddescription taken in conjunction with the accompanying drawings, inwhich:

FIG. 1A-1B illustrates exemplary stable water-in-silicone (W/O)emulsions comprising an emulsifier, a cell membrane fluidity enhancingagent, a fatty acid, a preservative, a bioactive agent, a pH bufferingsystem, an antioxidant, and a tocopherol. FIG. 1A shows an exemplaryphysicochemical orientation of the emulsifier, cell membrane fluidityenhancing agent, and fatty acid constituents, wherein only theemulsifier stabilizes the water and silicone interface. FIG. 1B shows asecond exemplary physicochemical orientation of the emulsifier, cellmembrane fluidity enhancing agent, and fatty acid constituents, whereinthe emulsifier, cell membrane fluidity enhancing agent, and fatty acidcooperatively stabilize the water and silicone interface.

FIG. 2A-2B illustrates an exemplary stable water-in-silicone (W/O)emulsion comprising an emulsifier, a cell membrane fluidity enhancingagent, a fatty acid, a preservative, a bioactive agent, a pH bufferingsystem, an antioxidant, a tocopherol, and an active agent. FIG. 2A showsan exemplary physicochemical orientation of the emulsifier, cellmembrane fluidity enhancing agent, and fatty acid constituents, whereinonly the emulsifier stabilizes the water and silicone interface. FIG. 2Bshows a second exemplary physicochemical orientation of the emulsifier,cell membrane fluidity enhancing agent, and fatty acid constituents,wherein the emulsifier, cell membrane fluidity enhancing agent, andfatty acid cooperatively stabilize the water and silicone interface.

FIG. 3A-3C illustrates optical imaging of Formulation #8. FIG. 3A is amacroscopic optical image of Formulation #8 on day 1. FIG. 3B is anoptical microscopic image of Formulation #8 on day 1. FIG. 3C is anoptical microscopic image of Formulation #8 on day 6. Scale bar is 300microns.

FIG. 4A-4C illustrates optical imaging of Formulation #9. FIG. 4A is amacroscopic optical image of Formulation #9 on day 1. FIG. 4B is anoptical microscopic image of Formulation #9 on day 1. FIG. 4C is anoptical microscopic image of Formulation #9 on day 31. Scale bar is 100microns.

FIG. 5A-5C illustrates optical imaging of Formulation #10. FIG. 5A is amacroscopic optical image of Formulation #10 on day 1. FIG. 5B is anoptical microscopic image of Formulation #10 on day 1. FIG. 5C is anoptical microscopic image of Formulation #10 on day 14. Scale bar is 100microns.

FIG. 6A-6E illustrates optical imaging of Formulations #13 and #14. FIG.6A is a macroscopic optical image of Formulation #13 on day 1. FIG. 6Bis an optical microscopic image of Formulation #13 on day 1. FIG. 6C isa macroscopic optical image of Formulation #14 on day 1. FIG. 6D is anoptical microscopic image of Formulation #14 on day 1. FIG. 6E is anoptical image of Formulation #14 showing phase separation. Scale bar is100 microns.

FIG. 7A-7D illustrates graphs of flow stress sweep analysis ofFormulation #9. FIG. 7A is a flow stress sweep of Formulation #9 at 25°C., wherein viscosity is plotted against shear rate. FIG. 7B is a flowstress sweep of Formulation #9 at 25° C., wherein viscosity is plottedagainst stress. FIG. 7C is a flow stress sweep of Formulation #9 at 37°C., wherein viscosity is plotted against shear rate. FIG. 7D is a flowstress sweep of Formulation #9 at 37° C., wherein viscosity is plottedagainst stress.

FIG. 8A-8B illustrates an oscillatory amplitude sweep of Formulation #9.FIG. 8A is an oscillatory amplitude sweep of Formulation #9 at 25° C.FIG. 8B is an oscillatory amplitude sweep of Formulation #9 at 37° C.

FIG. 9A-9B illustrates an oscillatory frequency sweep of Formulation #9.FIG. 9A is an oscillatory frequency sweep of Formulation #9 at 25° C.FIG. 9B is an oscillatory frequency sweep of Formulation #9 at 37° C.

FIG. 10 is an oscillatory temperature sweep of Formulation #9 from 20°C. to 40° C.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Certain exemplary embodiments will now be described to provide anoverall understanding of the principles of the compositions, methods,and kits disclosed herein. One or more examples of these embodiments areillustrated in the accompanying drawings. Those skilled in the art willunderstand that the compositions, methods, and kits specificallydescribed herein and illustrated in the accompanying drawings arenon-limiting exemplary embodiments and that the scope of the presentinvention is defined solely by the claims. The features illustrated ordescribed in connection with one exemplary embodiment may be combinedwith the features of other embodiments. Such modifications andvariations are intended to be included within the scope of the presentinvention.

Further, in the present disclosure, like-named components of theembodiments generally have similar features, and thus within aparticular embodiment each feature of each like-named component is notnecessarily fully elaborated upon.

The compositions provided herein are stable emulsions that are in theform of a relatively viscous, lubricious liquid, lotion, ointment, orcream. The compositions are stable as emulsions through expiry and canremain stable after application for up to about one week. Thecompositions can be used for a variety of purposes, as described herein,including for topical application, rectal application, and vulvovaginalapplication. Further, the compositions can be used with or without anactive and/or bioactive agent. More particularly, provided herein, interalia, are compositions comprising a water-in-silicone (W/O) emulsion,wherein the emulsion has a sterol at a concentration from about 0.1% toabout 4% by weight, of the total weight of the composition. Alsoprovided herein, are methods for preventing or treating vulvovaginal andother conditions (e.g., for rectal utility, dermatological utility,sunscreens, transdermal drug delivery, or ophthalmic utility) of asubject in need thereof, including applying the compositions (e.g., theemulsion comprising a sterol at a concentration from about 0.1% to about4% by weight, of the total weight of the composition), and kitsincluding the composition and reagents. Although the disclosure oftenrefers to composition being useful to treat vulvovaginal indications, itis understood that this is one of many exemplary uses of thecompositions disclosed herein. One skilled in the art will understandthat the described compositions have utility beyond vulvovaginalapplications, as described herein.

Definitions

The following definitions are included for the purpose of understandingthe present subject matter and for constructing the appended patentclaims. Abbreviations used herein have their conventional meaning withinthe chemical and biological arts.

Unless defined otherwise, all technical and scientific terms used hereinhave the meaning commonly understood by a person skilled in the art towhich this disclosure belongs. The following references provide one ofskill with a general definition of many of the terms used in thisdisclosure: The Cambridge Dictionary of Science and Technology (Walkered., 1988); The Glossary of Genetics, 5th Ed., R. Rieger et. al. (eds.),Springer Verlag (1991); and Hale & Marham, The Harper Collins Dictionaryof Biology (1991). As used herein, the following terms have the meaningsascribed to them below, unless specified otherwise.

Unless specifically stated or obvious from context, as used herein, theterm “or” is understood to be inclusive. Unless specifically stated orobvious from context, as used herein, the terms “a,” “an,” and “the” areunderstood to be singular or plural.

The term “about” when used in reference to numerical ranges, cutoffs, orspecific values is used to indicate that the recited values may vary byup to as much as 25% from the listed value. As many of the numericalvalues used herein are experimentally determined, it should beunderstood by those skilled in the art that such determinations can, andoften times will, vary among different experiments. The values usedherein should not be considered unduly limiting by virtue of thisinherent variation. The term “about” is used to encompass variations of±25% or less, variations of ±20% or less, variations of 10% or less,variations of ±5% or less, variations of ±1% or less, variations of±0.5% or less, or variations of ±0.1% or less from the specified value.About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%,1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwiseclear from the context, all numerical values provided herein aremodified by the term “about.”

As used herein, “administering to said subject” and similar termsindicate a procedure by which the described vulvovaginal compositionsare introduced into, instilled into, implanted in, applied into, orapplied onto a subject such that target cells, tissues, mucosa, orsegments of the body of the subject are contacted with the composition.

The term “administering,” as used herein, refers to any mode oftransferring, delivering, introducing, or transporting an agent, forexample, to a subject in need of treatment for a disease or condition.Such modes include, but are not limited to, oral, topical, intravenous,vaginal, mucosal, intraperitoneal, intramuscular, intradermal,intranasal, and subcutaneous administration.

Ranges provided herein are understood to be shorthand for all of thevalues within the range. For example, a range of 1 to 50 is understoodto include any number, combination of numbers, or sub-range from thegroup consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50,as well as all intervening decimal values between the aforementionedintegers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8,and 1.9. With respect to sub-ranges, “nested sub-ranges” that extendfrom either end point of the range are specifically contemplated. Forexample, a nested sub-range of an exemplary range of 1 to 50 maycomprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

As used herein, the term “analog” refers to a chemical compound that isstructurally similar to another but differs slightly in composition (asin the replacement of one atom by an atom of a different element or inthe presence of a particular functional group, or the replacement of onefunctional group by another functional group). Thus, an analog is acompound that is similar or comparable in function and appearance, butnot in structure or origin to the reference compound. As used herein,the term “derivative” refers to compounds that have a common corestructure, and are substituted with various groups as described herein.

As used herein, the term “emulsion” refers to a liquefied mixture thatcontains at least two distinguishable substances (or “phases”) that willnot readily mix and dissolve together. As used herein, a “emulsion”comprises a “continuous” phase (or “matrix”), which holds thereindiscontinuous droplets, bubbles, and/or particles of the other phase orsubstance. The term emulsion may thus refer to foams comprising gasbubbles suspended in a liquid continuous phase, emulsions in whichdroplets of a first liquid are dispersed throughout a continuous phasecomprising a second liquid with which the first liquid is immiscible,and continuous liquid phases throughout which solid particles aredistributed. As used herein, the term “emulsion” encompasses continuousliquid phases throughout which gas bubbles are distributed, continuousliquid phases throughout which solid particles (e.g., solid catalyst)are distributed, continuous phases of a first liquid throughout whichdroplets of a second liquid that is substantially insoluble in thecontinuous phase are distributed, and liquid phases throughout which anyone or a combination of solid particles, immiscible liquid droplets, andgas bubbles are distributed. Hence, an emulsion can exist as ahomogeneous mixture in some cases (e.g., liquid/liquid phase), or as aheterogeneous mixture (e.g., gas/liquid, solid/liquid, orgas/solid/liquid), depending on the nature of the materials selected forcombination.

As used herein, the term “stable” or “stability” refers to thewater-in-silicone emulsion as described herein. Stability can refer tothe ability of the emulsion to resist change in its properties over timeunder appropriate storage conditions. For example, the stability maytypically mean that the composition does not phase separate when storedat room temperature (e.g., approximately between 20° C. to 25° C.) forat least 1 month, or when stored in its final packaging at roomtemperature (e.g., approximately between 20° C. to 25° C.) for at least12 months. Other exemplary characteristics of stability include thestability of the final packaged product in terms of expiry. For example,the stability may mean that the product constituents (e.g. active orinactive ingredients) have not changed, degraded, or decomposed, theproduct properties (e.g. emulsion stability, zero-rate viscosity) asdefined on its Certificate of Analysis have not changed, the productpreservation system remains functional, or any combination thereof. Thestability of emulsions can be characterized using techniques describedherein, including for example, light scattering, optical microscopy,freeze-thaw cycling, centrifugation, and rheology.

Also, as used herein “stable” or “stability” refers to the compositioncomprising the water-in-silicone emulsion described herein (e.g., thecomposition comprising the emulsion and additional agents describedherein; “stable composition”). For example, the composition may includecarrier(s) and/or other material(s) suitable for the composition tocomprise a variety of active agents (e.g. active ingredients), and inwhich the active agents will be stable for an extended period of time asdescribed herein. In addition, the active agent according to someembodiments should be stable for a period of time in the composition asdescribed herein.

As used in the context of the composition of the present disclosure theterm “stable” means physical and chemical stability. Chemical stabilityrefers to chemical changes to an active or inactive agent itself (e.g.,degradation of the agents, oxidation of the agents). In embodiments ofthe present disclosure, storage or shelf-life of a composition is ameasure of chemical stability. Physical stability relates to mechanicalproperties, physical state (e.g., crystallinity, crystal structure), andactive agent (or drug) release properties.

The stability is measured after storing the composition of the currentdisclosure at temperature and relative humidity (RH) conditions of about25° C./60% RH to about 40° C./75% RH. Accelerated and real time testingof shelf-life of the composition is performed in order to confirm theshelf-life and set the product expiry. In addition, the shelf-life ofthe composition is also tested under expected packaging conditions.

The stability of the composition should be understood as meaningmaintenance of the homogeneous appearance of the composition, withoutphase separation, precipitation or flocculation of the particles, for atleast 6 months at 25° C. In other embodiments, the composition is stablefor at least 9 months, at least 12 months, at least 18 months, or atleast 24 months at 25° C.

As used herein, the term, “cream” may refer to a thick (high zero-rateviscosity) liquid, semi-liquid, or semi-solid formulation that may beused for therapeutic treatment of a disease, syndrome, or condition(i.e., a vulvovaginal disease, syndrome or condition).

As used herein, the term, “lotion” may refer to a moderately thick(moderate zero-rate viscosity) liquid, semi-liquid, or semi-solidformulation that may be used for therapeutic treatment of a disease,syndrome, or condition (i.e., a vulvovaginal disease, syndrome orcondition).

As used herein, the term “ointment” may refer to a highly viscous liquidor semi-liquid formulation that may be used for therapeutic treatment ofa disease, syndrome, or condition (i.e., a vulvovaginal disease,syndrome or condition).

“Liquid” as used herein is a dosage form consisting of a composition inits liquid state. A liquid is pourable; it flows and conforms to itscontainer at room temperature. Liquids display Newtonian orpseudoplastic flow behavior. In embodiments, a “semi-liquid” or“semi-solid” as used herein may have properties of both a liquid andanother formulation (i.e., a dispersion, a suspension, an emulsion, alotion, a cream and the like).

The term “moisturizing,” as used herein, refers to improving hydrationof a surface, such that water-binding capacity of the surface increases.The term “moisturize” or derivatives thereof, relates to the conversionor enhancement of the water contents of surfaces of a subject.

As used herein, “zero-rate viscosity” refers to a fluid or semi-solid'sresistance to flow when the shear rate approaches zero.

In the descriptions above and in the claims, phrases such as “at leastone of” or “one or more of” may occur followed by a conjunctive list ofelements or features. The term “and/or” may also occur in a list of twoor more elements or features. Unless otherwise implicitly or explicitlycontradicted by the context in which it is used, such a phrase isintended to mean any of the listed elements or features individually orany of the recited elements or features in combination with any of theother recited elements or features. For example, the phrases “at leastone of A and B;” “one or more of A and B;” and “A and/or B” are eachintended to mean “A alone, B alone, or A and B together.” A similarinterpretation is also intended for lists including three or more items.For example, the phrases “at least one of A, B, and C;” “one or more ofA, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, Balone, C alone, A and B together, A and C together, B and C together, orA and B and C together.” In addition, use of the term “based on,” aboveand in the claims is intended to mean, “based at least in part on,” suchthat an unrecited feature or element is also permissible.

By “ameliorate” is meant decrease, suppress, attenuate, diminish,arrest, or stabilize the development or progression of a disease orcondition such as, for example, a pseudo-allergic-type reaction.

The terms “subject,” “patient,” “individual,” and the like as usedherein are not intended to be limiting and can be generallyinterchanged. An individual described as a “subject,” “patient,”“individual,” and the like does not necessarily have a given disease,but may be merely seeking medical advice. The terms “subject,”“patient,” “individual,” and the like as used herein include all membersof the animal kingdom that may suffer from the indicated disorder. Insome aspects, the subject is a mammal, and in some aspects, the subjectis a human.

The term “around” when used in reference to the site of administrationof the described vulvovaginal compositions should be understood by thoseskilled in the art to mean administered to the anatomical area ofinterest within the limits of traditionally practiced procedures. Forexample, administration “around” the relevant anatomical site refers toa location that is not directly within or on the site, but sufficientlyclose to the site to provide a physiological or therapeutically relevanteffect thereon. Those of ordinary skill in the art can readily determinethe maximum distance from a given anatomical site that will besufficient to provide a physiological or therapeutically relevant effectusing a vulvovaginal composition according to the present disclosure.

“Pharmaceutically acceptable” refers to those properties and substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance, and bioavailability.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to a subject, or aids absorption by a subject, or improvesstability or other properties of the active agent, and can be includedin the compositions of the present invention without causing asignificant adverse toxicological effect on the patient. Unlessindicated to the contrary, the terms “active agent,” “activeingredient,” “therapeutically active agent,” “therapeutic agent,”“bioactive agent” and like are used synonymously. Non-limiting examplesof pharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, polyethyleneglycol, and colors, and the like. Such preparations can be sterilizedand, if desired, mixed with auxiliary agents such as lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, coloring, and/or aromaticsubstances and the like that do not deleteriously react with thecompounds of the invention. One of skill in the art will recognize thatother pharmaceutical excipients are useful in the present invention.

As used herein, the terms “active agent,” “active ingredient,”“therapeutically active agent,” “therapeutic agent,” “bioactive agent”mean “possessing biological activity,” such as a biochemical,pharmacological or a therapeutic activity. In some embodiments, thebioactivity is providing symptom relief, treating underlyingpathophysiology or infection of the vulvovaginal anatomy, orprophylactically protecting the vulvovaginal anatomy in a subject. Incertain embodiments, the bioactivity is enhancement of skin functionand/or effect on skin homeostasis. In other examples, the bioactivity isenhancement of the rectal system and anatomy. In yet other examples, thebioactivity is enhancement of the ophthalmic system and anatomy. Also,as provided, the bioactivity is for the treatment or prevention of sundamage (e.g., sunscreen).

In certain embodiments, the biological activity is, without limitation,analgesic, antifungal, antiviral, anti-infective, anti-inflammatory,antineoplastic, immunostimulating, immunosuppressing, immunomodulating,endocrine modulating, enhancement of cell viability, cell membranefluidizing, antioxidative, oxygen carrier, contraceptive, cellrecruitment, cell attachment, angiogenesis, wound healing activity,mobilization of host stem or progenitor cells, cellular proliferation,stimulation of cell migration to injury sites, amelioration of cell andtissue fibrosis, or any combination thereof.

“Therapeutically effective dose” refers to an amount of a composition,as described herein, effective to achieve a particular physiological,biological or therapeutic result such as, but not limited to, thephysiological, biological or therapeutic results disclosed, described,or exemplified herein. These physiological, biological or therapeuticresults include, but are not limited to, restoring the pH, providinglubrication, promoting healthy flora, or eliminating infections (e.g.,restoring pH of the vagina, providing lubrication to the vagina,promoting healthy flora, eliminating infections, or providingcontraception). The therapeutically effective dose may vary according tofactors such as the disease state, age, sex, and weight of theindividual, as well as, the ability of the composition to cause thedesired response in a subject. Such results may include, but are notlimited to, providing symptom relief, treating underlyingpathophysiology, or prophylactically protecting the vagina, asdetermined by any means suitable in the art.

The terms “treat,” “treating” or “treatment” refer to any success orindicia of success in the attenuation or amelioration of an infection,pathology or condition, including any objective or subjective parametersuch as abatement, abrogation, remission, diminishing of symptoms ormaking the infection, pathology, or condition more tolerable to thepatient, slowing the disease progression, making the condition lessdebilitating, or improving a subject's physical or mental well-being.The treatment may be assessed by objective or subjective parameters;including the results of a physical examination.

As used herein, “prophylactically protect” or “prophylacticallyprotecting” means to treat a condition (e.g., a vulvar or vaginalcondition) in a preventative manner.

As used herein, “incorporated within” means that the emulsifier, thecell membrane fluidity enhancing agent, the fatty acid, thepreservative, and at least one of, the bioactive agent, the pH bufferingsystem, the viscosity enhancing agent, the antioxidant, the tocopherol,the ceramide, the active agent, or any combination thereof, are at leastpartially covered by, contained within, dispersed within, distributedwithin, encased within, or entrapped by the water and silicone emulsion.Depending on the type of constituent, excipient, or agent, theconstituent, excipient, or agent may be located in the aqueous phase,the silicone phase, or both.

Each embodiment disclosed herein is contemplated as being applicable toeach of the other disclosed embodiments. Thus, all combinations of thevarious elements described herein are within the scope of the invention.

Other features and advantages of the invention will be apparent from thefollowing description of the preferred embodiments thereof, and from theclaims. Unless otherwise defined, all technical and scientific termsused herein have the same meaning as commonly understood by one ofordinary skill in the art to which this invention belongs. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described below. All publishedforeign patents and patent applications cited herein are incorporatedherein by reference. Genbank and NCBI submissions indicated by accessionnumber cited herein are incorporated herein by reference. All otherpublished references, documents, manuscripts and scientific literaturecited herein are incorporated herein by reference. In the case ofconflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

Compositions

The present disclosure provides compositions comprising awater-in-silicone (W/O) emulsion comprising a cell membrane fluidityenhancing agent. In embodiments, the cell membrane fluidity enhancingagent is at a concentration from about 0.1% to about 4% by weight, ofthe total weight of the composition.

In embodiments, the compositions disclosed herein are stable, water andsilicone emulsions that include, but are not limited to, creams,lotions, ointments, moisturizers, or personal lubricants.

Suitable water and silicone emulsions include, but are not limited to,water-in-silicone (W/O), silicone-in-water (0/W) orwater-in-silicone-in-water (W/O/W). In some embodiments, the water andsilicone emulsion is a W/0 emulsion. In preferred examples, a suitableemulsion is a water-in-silicone (W/O) emulsion. For example, withoutintent to be limiting, W/0 emulsions can have an aqueous phasecomprising up to 50% by weight of water, inclusive, and a silicone phasecomprising between 20% by weight and 95% by weight of silicone,inclusive.

In some examples, the water-in-silicone emulsion comprises a siliconephase, wherein the silicone phase comprises a silicone oil, a siliconewax, a silicone gum, or any combination thereof.

When creating a water-in-silicone emulsion, a number of silicone oils,silicone gums, or silicone waxes may be selected from those known in theart. For the purposes of this disclosure, suitable silicone oilsinclude, but are not limited to, dimethicone, cyclomethicone, caprylylmethicone, cyclopentasiloxane, cyclohexasiloxane or any combinationthereof. For the purposes of this disclosure, suitable silicone gumsinclude, but are not limited to, dimethiconol. For the purposes of thisdisclosure, suitable silicone waxes include, but are not limited to,stearyl dimethicone.

In some embodiments, the dispersant phase (e.g., the phase used todisperse small particles or droplets) may be stabilized to create astable emulsion. Exemplary agents used to stabilize to create a stableemulsion include, but are not limited to, emulsifiers andco-emulsifiers. Suitable emulsifiers and co-emulsifiers for stabilizingthe resulting emulsion (e.g., liquid-liquid droplets) include, but arenot limited to, a sterol, a sterol derivative, cholesterol, cholesterolderivatives, glyceryl stearate, glyceryl monostearate, sorbitanmonolaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitantristearate, sorbitan monooleate, sorbitan trioleate, polyoxyethylenesorbitan monolaurate, polyoxyethylene sorbitan monopalmitate,polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitantristearate, polyoxyethylene sorbitan monooleate, polyoxyethylenesorbitan trioleate, polyoxyethylene monolaurate, polyoxyethylenemonostearate, polyoxyethylene monopalmitate, polyoxyethylene monooleate,lecithin, PEG/PPG-18/18 dimethicone, cetyl PEG/PPG-10/1 dimethicone,dimethicone copolyol, octyldodecanol, poly(vinyl alcohol), Pluronic,Poloxamer, Carbomer, isopropyl myristate, or any combination thereof.

In some examples, the compositions described herein can in include oneor more (e.g., at least one) cell membrane fluidity enhancing agents toenable (e.g., promote) increased cell membrane fluidity, increasedcellular penetration, increased absorption of desired constituents,excipients or agents, increased lubrication and moisturization, or anycombination thereof. Suitable cell membrane fluidity enhancing agentsinclude, but are not limited to, sterols (e.g., steroid alcohols).Sterols are a subgroup of steroids with a hydroxyl group at the3-position of the A-ring. They are amphipathic lipids synthesized fromacetyl-coenzyme A. The sterol chemical structure is depicted below:

The one or more cell membrane fluidity enhancing agents can beincorporated within the emulsion. In some embodiments, the one or morecell membrane fluidity enhancing agents are incorporated within theaqueous phase of the emulsion. In other embodiments, the one or morecell membrane fluidity enhancing agents are incorporated within thesilicone phase of the emulsion. In yet other embodiments, the one ormore cell membrane fluidity enhancing agents are incorporated withinboth the aqueous phase and the silicone phase of the emulsion.

In some embodiments, the cell membrane fluidity enhancing agent can beformulated to comprise up to 0.1% by weight, inclusive, of thecomposition. In some embodiments, the cell membrane fluidity enhancingagent can be formulated to comprise up to 0.25% by weight, inclusive, ofthe composition. In some embodiments, the cell membrane fluidityenhancing agent can be formulated to comprise up to 0.5% by weight,inclusive, of the composition. In some embodiments, the cell membranefluidity enhancing agent can be formulated to comprise up to 1% byweight, inclusive, of the composition. In some embodiments, the cellmembrane fluidity enhancing agent can be formulated to comprise up to1.5% by weight, inclusive, of the composition. In some embodiments, thecell membrane fluidity enhancing agent can be formulated to comprise upto 2% by weight, inclusive, of the composition. In some embodiments, thecell membrane fluidity enhancing agent can be formulated to comprise upto 2.5% by weight, inclusive, of the composition. In some embodiments,the cell membrane fluidity enhancing agent can be formulated to compriseup to 3% by weight, inclusive, of the composition. In some embodiments,the cell membrane fluidity enhancing agent can be formulated to compriseup to 3.5% by weight, inclusive, of the composition. In someembodiments, the cell membrane fluidity enhancing agent can beformulated to comprise up to 4% by weight, inclusive, of thecomposition. In some embodiments, the cell membrane fluidity enhancingagent can be formulated to comprise up to 4.5% by weight, inclusive, ofthe composition. In some embodiments, the cell membrane fluidityenhancing agent can be formulated to comprise up to 5% by weight,inclusive, of the composition. In some embodiments, the cell membranefluidity enhancing agent can be formulated to comprise up to 5.5% byweight, inclusive, of the composition.

Throughout the present disclosure, the phrase “the cell membranefluidity enhancing agent” can refer to more than one cell membranefluidity enhancing agent if more than one such agent is present in thecomposition. For example, when only one cell membrane fluidity enhancingagent is incorporated within the emulsion, a reference to “50% by weightof the cell membrane fluidity enhancing agent” means that there is 50%of the sole cell membrane fluidity enhancing agent present. When morethan one cell membrane fluidity enhancing agent is incorporated withinthe emulsion, language referring to “50% by weight of the cell membranefluidity enhancing agent,” means that 50% of the total complement ofcell membrane fluidity enhancing agents is incorporated within theemulsion. Thus, if the composition includes 1 mg of a first cellmembrane fluidity enhancing agent and 1 mg of a second cell membranefluidity enhancing agent, then “50% by weight of the cell membranefluidity enhancing agent” can mean that 50% of the total complement of 2mg of cell membrane fluidity enhancing agents is incorporated within theemulsion.

The term “sterol” as used herein may refer to natural or synthetic plantor animal sterols. Exemplary sterols include cholesterol, cholesterolderivatives, phytosterols, or any combination thereof. Additionalsterols include diosgenin, stigmastanol, tigogenin, α-sitosterol,β-sitosterol, stigmasterol, ergosterol, campesterol, oleanoic acids,soyasapogenols (e.g., soyasapogenol A or soyasapogenol B),protoascigenin, and protopanaxadiols. In some embodiments, the sterol ischolesterol. When the sterol is cholesterol, its physiochemical andbiochemical properties enable it to uniquely and simultaneously functionas a cell membrane fluidity enhancing agent, as an emulsifier that playsa critical role in stabilizing the water-in-silicone droplet interface,and as a bioactive agent.

In other examples, the compositions described herein can include one ormore (e.g., at least one) fatty acids. Fatty acids are carboxylic acidswith a long aliphatic chain, which is either saturated or unsaturated.Most naturally occurring fatty acids have an unbranched chain of an evennumber of carbon atoms, e.g., from 4 to 28 carbon atoms. In embodiments,the fatty acids may facilitate cellular interactions with theformulation. Suitable fatty acids include, but are not limited to,caprylic acid, lauric acid, myristic acid, caproleic acid, lauroleicacid, myristoleic acid, palmitoleic acid, oleic acid, stearic acid,palmitic acid, linoleic acid, arachidonic acid, stearidonic acid,docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), or anycombination thereof.

The one or more fatty acids can be incorporated within the emulsion. Insome embodiments, the one or more fatty acids are incorporated withinthe aqueous phase of the emulsion. In other embodiments, the one or morefatty acids are incorporated within the silicone phase of the emulsion.In yet other embodiments, the one or more fatty acids are incorporatedwithin both the aqueous phase and the silicone phase of the emulsion.

In some embodiments, the fatty acid can be formulated to comprise up to0.1% by weight, inclusive, of the composition. In some embodiments, thefatty acid can be formulated to comprise up to 0.25% by weight,inclusive, of the composition. In some embodiments, the fatty acid canbe formulated to comprise up to 0.5% by weight, inclusive, of thecomposition. In some embodiments, the fatty acid can be formulated tocomprise up to 1% by weight, inclusive, of the composition. In someembodiments, the fatty acid can be formulated to comprise up to 1.5% byweight, inclusive, of the composition. In some embodiments, the fattyacid can be formulated to comprise up to 2% by weight, inclusive, of thecomposition. In some embodiments, the fatty acid can be formulated tocomprise up to 2.5% by weight, inclusive, of the composition. In someembodiments, the fatty acid can be formulated to comprise up to 3% byweight, inclusive, of the composition. In some embodiments, the fattyacid can be formulated to comprise up to 4% by weight, inclusive, of thecomposition. In some embodiments, the fatty acid can be formulated tocomprise up to 5% by weight, inclusive, of the composition. In someembodiments, the fatty acid can be formulated to comprise up to 6% byweight, inclusive, of the composition. In some embodiments, the fattyacid can be formulated to comprise up to 8% by weight, inclusive, of thecomposition. In some embodiments, the fatty acid can be formulated tocomprise up to 10% by weight, inclusive, of the composition.

Throughout the present disclosure, the phrase “the fatty acid” can referto more than one fatty acid if more than one such agent is present inthe composition. For example, when only one fatty acid is incorporatedwithin the emulsion, a reference to “50% by weight of the fatty acid”means that there is 50% of the sole fatty acid present. When more thanfatty acid is incorporated within the emulsion, language referring to“50% by weight of the fatty acid” means that 50% of the total complementof fatty acids is incorporated within the emulsion. Thus, if thecomposition includes 1 mg of a first fatty acid and 1 mg of a secondfatty acid, then “50% by weight of the fatty acid” can mean that 50% ofthe total complement of 2 mg of fatty acids is incorporated within theemulsion.

In other examples, the phrase “the fatty acid” can refer to more thanone fatty acid derivative if more than one such agent is present in thecomposition. Suitable fatty acid derivatives include, but are notlimited to, a caprylic acid derivative, a lauric acid derivative, amyristic acid derivative, a caproleic acid derivative, a lauroleic acidderivative, a myristoleic acid derivative, a palmitoleic acidderivative, an oleic acid derivative, a stearic acid derivative, apalmitic acid derivative, a linoleic acid derivative, an arachidonicacid derivative, a stearidonic acid derivative, or any combinationthereof.

In embodiments, the disclosed compositions can include one or morepreservatives. The preservatives, for example, may be used to controlstability and expiry of the formulation, where stability and expiry areevaluated by methods known to those skilled in the art. Suitablepreservatives include, but are not limited to, sorbic acid, potassiumsorbate, boric acid, sodium borate, benzoic acid, sodium benzoate,benzalkonium chloride, benzethonium chloride, EDTA, parabens, or anycombination thereof.

The one or more preservatives can be incorporated within the compositioncomprising the emulsion. In some embodiments, the one or morepreservatives are incorporated within the aqueous phase of the emulsion.In other embodiments, the one or more preservatives are incorporatedwithin the silicone phase of the emulsion. In yet other embodiments, theone or more preservatives are incorporated within both the aqueous phaseand the silicone phase of the emulsion.

In some embodiments, the preservative can be formulated to comprise upto 0.01% by weight, inclusive, of the emulsion. In some embodiments, thepreservative can be formulated to comprise up to 0.025% by weight,inclusive, of the composition. In some embodiments, the preservative canbe formulated to comprise up to 0.05% by weight, inclusive, of thecomposition. In some embodiments, the preservative can be formulated tocomprise up to 0.1% by weight, inclusive, of the composition. In someembodiments, the preservative can be formulated to comprise up to 0.2%by weight, inclusive, of the composition. In some embodiments, thepreservative can be formulated to comprise up to 0.5% by weight,inclusive, of the composition. In some embodiments, the preservative canbe formulated to comprise up to 1% by weight, inclusive, of thecomposition. In some embodiments, the preservative can be formulated tocomprise up to 2% by weight, inclusive, of the composition. In someembodiments, the preservative can be formulated to comprise up to 4% byweight, inclusive, of the composition.

Throughout the present disclosure, the phrase “the preservative” canrefer to more than one preservative if more than one such agent ispresent in the composition. For example, when only one preservative isincorporated within the emulsion, a reference to “50% by weight of thepreservative” means that there is 50% of the sole preservative present.When more than preservative is incorporated within the emulsion,language referring to “50% by weight of the preservative” means that 50%of the total complement of preservatives is incorporated within theemulsion. Thus, if the composition includes 1 mg of a first preservativeand 1 mg of a second preservative, then “50% by weight of thepreservative” can mean that 50% of the total complement of 2 mg ofpreservatives is incorporated within the emulsion.

The disclosed compositions can include bioactive agents. In embodiments,the bioactive agents may affect the biochemistry or cellular physiologyof the desired condition (e.g., vulvar or vaginal anatomy.) Suitablebioactive agents include, but are not limited to, glycogen, cholesterol,lactic acid, lactate salts, tocopherols, or any combination thereof.Additional bioactive agents are described in detail below.

Throughout the present disclosure, the phrase “the bioactive agent” canrefer to more than one bioactive agent if more than one such agent ispresent in the composition. For example, one or more bioactive agentscan be incorporated within the emulsion. In some embodiments, the one ormore bioactive agents are incorporated within the aqueous phase of theemulsion. In other embodiments, the one or more bioactive agents areincorporated within the silicone phase of the emulsion. In yet otherembodiments, the one or more bioactive agents are incorporated withinboth the aqueous phase and the silicone phase of the emulsion.

In some examples, bioactive agent can be used in the amount of about0.01% by weight to about 100% by weight, based on the total weight ofthe composition. In other examples, the active agent can be used inamount from about 0.01% by weight to about 90% by weight, from about0.01% by weight, to about 80% by weight, from about 0.01% by weight toabout 70% by weight, from about 0.01% by weight to about 60% by weight,from about 0.01% by weight to about 50% by weight, from about 0.01% byweight to about 40% by weight, from about 0.01% by weight to about 30%by weight, from about 0.01% by weight to about 20% by weight, from about0.01% by weight, to about 10% by weight, from about 0.01% by weight toabout 1% by weight, or from about 0.01% by weight to about 0.1% byweight of the composition.

In embodiments, the disclosed composition can include one or more pHbuffering systems. For example, the pH buffering systems may be capableof restoring the physiological pH (e.g., of the vagina). Suitable pHbuffering systems include, but are not limited to, lactic acid and saltsof lactic acid. In some embodiments, the pH buffering system is lacticacid and sodium lactate. In other embodiments, the pH buffering systemis lactic acid and calcium lactate. Further, the composition (e.g., avulvovaginal composition) can have a pH of 3.8 and the pH bufferingsystem can have a buffering capacity within the range of 3.5-4.2.

In examples, the present disclosure includes compositions (e.g.,emulsion) having a pH buffering system comprising one or more pHadjusting agents. The pH adjusting agent may be, for example, sodiumhydroxide, hydrochloric acid, citric acid, malic acid, tartaric acid,acetic acid, phosphoric acid, maleic acid, glycine, sodium lactate,lactic acid, sodium citrate, ascorbic acid, sodium acetate, acetic acid,sodium bicarbonate, sodium carbonate, carbonic acid, sodium succinate,succinic acid, sodium benzoate, benzoic acid, sodium phosphates,tris(hydroxymethyl)aminomethane, histidine, histidine hydrochloride, orany combination(s) thereof.

Compounds useful as pH adjusting agents include, but are not limited to,boric acid, sodium borate, sodium phosphate (including mono-, di-,tri-basic phosphate, and mixtures thereof). Any other physiologicallyrelevant buffers can be used to stabilize the pH level of thecomposition by conferring physiological pH approved for medicines. Sincesaid buffers are just examples and these buffers are well known in thefield, a person skilled in the art can choose proper buffers that can beused for the composition of the present disclosure.

In examples, the pH of the formulation is from about 2 to about 9. Inother examples, the pH is in a range from about 3 to 9, or from about 4to 9, or from about 5 to 9, or from about 6 to 9, or from about 7 to 9,or from about 8 to 9. In other examples, the pH is in a range from about3 to 8, or from about 4 to 8, or from about 5 to 8, or from about 6 to8, or from about 7 to 8. In other examples, the pH is in a range fromabout 3 to 7, or from about 4 to 7, or from about 5 to 7, or from about6 to 7. In other examples, the pH is in a range from about 3 to 6, orfrom about 4 to 6, or from about 5 to 6.

Also as described herein, the disclosed compositions can include one ormore viscosity enhancing agents, e.g., to obtain desired mechanicalproperties. In some examples, the mechanical properties can be measuredby rheological methods known by those skilled in the art. Suitableviscosity enhancing agents include, but are not limited to,hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, ethylcellulose, hyaluronic acid, sodium hyaluronate, Carbomer, Carbopol,poly(acrylic acid), polycarbophil, guar gum, xanthan gum, or anycombination thereof.

In embodiments, the zero-rate viscosity of the stable water-in-siliconeemulsion can be between 100 Pa-s and 1000 kPa-s. For determination ofthe zero-rate viscosity of the emulsion, suitable characterizationmethods include, but are not limited to, rheometry and viscometry.

Throughout the present disclosure, the phrase “the viscosity enhancingagent” can refer to more than one viscosity enhancing agent if more thanone such agent is present in the composition. For example, one or moreviscosity enhancing agents can be incorporated within the emulsion. Insome embodiments, the one or more viscosity enhancing agents areincorporated within the aqueous phase of the emulsion. In otherembodiments, the one or more viscosity enhancing agents are incorporatedwithin the silicone phase of the emulsion. In yet other embodiments, theone or more viscosity enhancing agents are incorporated within both theaqueous phase and the silicone phase of the emulsion.

The disclosed compositions can include one or more antioxidants toenhance formulation stability, affect the cellular physiology, or anycombination thereof. Suitable antioxidants include, but are not limitedto, ascorbic acid, sodium ascorbate, a polyphenol, or any combinationthereof.

Throughout the present disclosure, the phrase “the antioxidant” canrefer to more than one antioxidant if more than one such agent ispresent in the composition. For example, one or more antioxidants can beincorporated within the emulsion. In some embodiments, the one or moreantioxidants are incorporated within the aqueous phase of the emulsion.In other embodiments, the one or more antioxidants are incorporatedwithin the silicone phase of the emulsion. In yet other embodiments, theone or more antioxidants are incorporated within both the aqueous phaseand the silicone phase of the emulsion.

The disclosed compositions can include one or more tocopherols to affectthe cellular physiology, lubrication, or any combination thereof.Suitable tocopherols include, but are not limited to, alpha-tocopherol,vitamin E, vitamin E-TPGS, tocopheryl acetate, or any combinationthereof. Tocopherols (e.g. vitamin E) can provide lubricity, antioxidantproperties, or any combination thereof.

Throughout the present disclosure, the phrase “the tocopherol” can referto more than one tocopherol if more than one such agent is present inthe composition. For example, one or more tocopherols can beincorporated within the emulsion. In some embodiments, the one or moretocopherols are incorporated within the aqueous phase of the emulsion.In other embodiments, the one or more tocopherols are incorporatedwithin the silicone phase of the emulsion. In yet other embodiments, theone or more tocopherols are incorporated within both the aqueous phaseand the silicone phase of the emulsion.

The disclosed compositions can include one or more active agents toprovide symptom relief, treat underlying pathophysiology or infection,or prophylactically protect the anatomy (e.g., the vagina) of thesubject. Suitable classes of active agents include, but are not limitedto, antifungals, antibiotics, spermicides, estrogens, estrogenderivatives, progesterone, progesterone derivatives, estrogenprecursors, steroids, anti-inflammatories, antivirals/antiretrovirals(e.g. CCR5 antagonists, nucleoside reverse transcriptase inhibitors(NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs),protease inhibitors (PIs), fusion inhibitors, integrase inhibitors,post-attachment inhibitors, pharmacokinetic enhancers), or anycombination thereof. Suitable active agents include, but are not limitedto, miconazole, metronidazole, clotrimazole, estradiol, prasterone,nonoxynol-9, or any combination thereof. In some embodiments, the activeagent is miconazole. In some embodiments, the active agent ismetronidazole. In some embodiments, the active agent is clotrimazole. Insome embodiments, the active agent is estradiol. In some embodiments,the active agent is prasterone. In some embodiments, the active agent isnonoxynol-9.

The disclosed compositions can include one or more active agents totreat or protect the skin of the subject. Suitable classes of activeagents include, but are not limited to, antibiotics, antimicrobials,antifungals, antiseptics, local anesthetics, analgesics,anti-inflammatories, immunosuppressants, steroids, corticosteroids,calcineurin inhibitors, PDE4 inhibitors, salicylic acid, retinoids,antihistamines, benzoyl peroxide, nanocrystalline silver, or anycombination thereof.

Exemplary antibiotics include, but are not limited to amoxicillin,doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole,azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanate,and levofloxacin. Additional antibiotcs include Mikacin, Gentamicin,Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin,Spectinomycin(Bs), Geldanamycin, Herbimycin, Rifaximin, Loracarbef,Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem, Cefadroxil,Cefazolin, Cephradine, Cephapirin, Cephalothin, Cefalexin, Cefaclor,Cefoxitin Cefotetan, Cefamandole, Roxithromycin, Telithromycin,Spiramycin, Fidaxomicin, Furazolidone, Nitrofurantoin(Bs), Linezolid,Posizoli, Radezolid, Torezolid, Ampicillin, Azlocillin, Dicloxacillin,Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin,Penicillin G, Penicillin V, Piperacillin, Penicillin G, Temocillin,Ticarcillin, Ampicillin/sulbactam, Piperacillin/tazobactam,Ticarcillin/clavulanate, Bacitracin, Colistin, Polymyxin B,Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin,Norfloxacin, Ofloxacin, Trovafloxacin, Minocycline, Oxytetracycline,Tetracycline, Clofazimine, Dapsone, Capreomycin, CycloserinemPyrazinamide, Rifampicin, Rifabutin, Rifapentine, Streptomycin,Metronidazole, and Mupirocin

Exemplary antimicrobials include, but are not limited to amoxicillin,doxycycline. Cephalexin, ciprofloxacin, clindamycin, metronidazole,azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanate,and levofloxacin.

Exemplary antifungals include, but are not limited to, miconazole,clotrimazole, amphotericin B, ketoconazole, fluconazole, isavuconazole,itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin,micafungin, and flucytosine.

Exemplary antiseptics include ethanol, sodium hypochlorite,chlorhexidine, hexachlorophene, povidone iodine, sodium hypochlorite,sodium hypochlorite, benzethonium chloride, triclosan, oxychlorosenesodium, benzalkonium chloride, and silver nitrate.

Exemplary local anesthetics include amylocaine, ambucaine, articaine,benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine,chloroprocaine, cinchocaine(INN), cocaine, cyclomethycaine, dibucaine,diperodon, dimethocaine, eucaine, etidocaine, hexylcaine, fomocaine,fotocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine(lignocaine), mepivacaine, meprylcaine, metabutoxycaine, nitracaine,orthocaine, oxetacaine(oxethazaine), oxybuprocaine, paraethoxycaine,phenacaine, piperocaine, piridocain, pramocaine, prilocaine, primacaine,procaine, procainamide, proparacaine, propoxycaine, pyrrocaine,quinisocaine(INN), ropivacaine, trimecaine, tetracaine, tolycaine, andtropacocaine.

Exemplary analgesics include codeine, fentanyl, hydrocodone (Hysingla,Zohydro, Hydrocodone/acetaminophen (Lorcet, Lortab, Norco, Vicodin),Hydromorphone (Dilaudid, Exalgo), Meperidine (Demerol), Methadone(Dolophine, Methadose), Morphine (Kadian, MS Contin, Morphabond),Oxycodone (OxyContin, Oxaydo), Oxycodone and acetaminophen (Percocet,Roxicet), and Oxycodone and naloxone.

Exemplary anti-inflammatories include celecoxib (Celebrex), diclofenac(Cambia, Cataflam, Voltaren-XR, Zipsor, Zorvolex), diflunisal (Dolobid),etodolac (Lodine), ibuprofen (Motrin, Advil), indomethacin (Indocin),ketoprofen (Active-Ketoprofen, ketorolac, nabumetone naproxen (Aleve,Anaprox, Naprelan, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene),salsalate, sulindac, and tolmetin.

Exemplary immunosuppressants include corticosteroids (e.g., prednisone(Deltasone, Orasone), budesonide (Entocort EC), prednisolone, and(Millipred)), Janus kinase inhibitors (e.g. tofacitinib (Xeljanz)),Calcineurin inhibitors, e.g., cyclosporine (Neoral, Sandimmune,SangCya), and tacrolimus (Astagraf XL, Envarsus XR, Prograf), mTORinhibitors, e.g., sirolimus (Rapamune), and everolimus (Afinitor,Zortress), IMDH inhibitors, e.g., azathioprine (Azasan, Imuran),leflunomide (Arava), and mycophenolate (CellCept, Myfortic), biologics,e.g., abatacept (Orencia), adalimumab (Humira), anakinra (Kineret),certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi),infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri),rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra),ustekinumab (Stelara), vedolizumab (Entyvio), and monoclonal antibodies,e.g., basiliximab (Simulect), daclizumab (Zinbryta), and muromonab(Orthoclone OKT3).

Exemplary calcineurin inhibitors include astagraf XL, cyclosporine,cyclosporine ophthalmic, Elidel, Envarsus XR, Gengraf, Hecoria, Neoral,pimecrolimus, Prograf, Protopic, Restasis, Sandimmune, tacrolimus, andtacrolimus ointment.

Exemplary phosphodiesterase 4 (PDE4) inhibitors include Adibendan,Aminophylline, Aminophylline dehydrate, Amipizone, Apremilast,Arofylline, Atizoram, Befuraline, Bemarinone hydrochloride, Bemoradan,Benafentrine, Bucladesine, Buflomedil, Buquineran, CC-1088, Carbazeran,Catramilast, Cilomilast, Cilostamide, Cilostazol, Cipamfylline,Crisaborole, Daxalipram, Denbufylline, Dimabefylline, Diniprofylline,Dipyridamole, Doxofylline, Drotaverine, Dyphylline, Enoximone,Etamiphyllin, Etofylline, Filaminast, Flufylline, Fluprofylline,Furafylline, Imazodan, Imazodan hydrochloride, Inamrinone, Inamrinonelactate, Isbufylline, Lirimilast, Lisofylline, Lomifylline, Medorinone,Metescufylline, Midaxifylline, Milrinone, Milrinone lactate, Motapizone,Nanterinone, Nestifylline, Nitraquazone, Oglemilast, Oglemilast Sodium,Olprinone, Oxagrelate, Oxtriphylline, Papaverine, Papaverinehydrochloride, Papaverine sulfate, Parogrelil, Pelrinone hydrochloride,Pentifylline, Pentoxifylline, Perbufylline, Piclamilast, Pimefylline,Pimobendan, Piroximone, Prinoxodan, Proxyphylline, Pumafentrine,Quazinone, Quazodine, Revamilast, Revizinone, Roflumilast, Rolipram,Ronomilast, Saterinone, Senazodan, Siguazodan, Tetomilast, Tofimilast,Trapidil, Vesnarinone, and Zardaverine.

The disclosed compositions can include one or more active agents toprovide symptom relief or treat underlying pathophysiology, or protectthe anatomy (e.g., the rectum) of the subject. Suitable classes ofactive agents include, but are not limited to, vasoconstrictors,anti-inflammatories, steroids, local anesthetics, alpha-adrenergicreceptor agonists, onabotulinumtoxinA, calcium channel inhibitors,nitrates, or any combination thereof.

The one or more active agents can be incorporated within the emulsion.In some embodiments, the one or more active agents are incorporatedwithin the aqueous phase of the emulsion. In other embodiments, the oneor more active agents are incorporated within the silicone phase of theemulsion. In yet other embodiments, the one or more active agents areincorporated within both the aqueous phase and the silicone phase of theemulsion.

In some embodiments, the active agent can be formulated to be present inan amount typical for such an agent. For example, the agent can beformulated to comprise up to 0.01% by weight, inclusive, of thecomposition. In some embodiments, the active agent can be formulated tocomprise up to 0.025% by weight, inclusive, of the composition. In someembodiments, the active agent can be formulated to comprise up to 0.05%by weight, inclusive, of the composition. In some embodiments, theactive agent can be formulated to comprise up to 0.1% by weight,inclusive, of the composition. In some embodiments, the active agent canbe formulated to comprise up to 0.2% by weight, inclusive, of thecomposition. In some embodiments, the active agent can be formulated tocomprise up to 0.5% by weight, inclusive, of the composition. In someembodiments, the active agent can be formulated to comprise up to 1% byweight, inclusive, of the composition. In some embodiments, the activeagent can be formulated to comprise up to 2% by weight, inclusive, ofthe composition. In some embodiments, the active agent can be formulatedto comprise up to 4% by weight, inclusive, of the composition. In someembodiments, the active agent can be formulated to comprise up to 6% byweight, inclusive, of the composition. In some embodiments, the activeagent can be formulated to comprise up to 8% by weight, inclusive, ofthe composition. In some embodiments, the active agent can be formulatedto comprise up to 10% by weight, inclusive, of the composition.

Throughout the present disclosure, the phrase “the active agent” canrefer to more than one active agent if more than one such agent ispresent in the composition. For example, when only one active agent isincorporated within the emulsion, a reference to “50% by weight of theactive agent” means that there is 50% of the sole active agent present.When more than active agent is incorporated within the emulsion,language referring to “50% by weight of the active agent” means that 50%of the total complement of active agents is incorporated within theemulsion. Thus, if the composition includes 1 mg of a first active agentand 1 mg of a second active agent, then “50% by weight of the activeagent” can mean that 50% of the total complement of 2 mg of activeagents is incorporated within the emulsion.

The compositions of the present invention can contain a safe andeffective amount of a conditioning agent, for example, humectants,emollients, moisturizers, and skin conditioners. A variety of thesematerials can be employed and can be present at a level of from about0.01% to about 80%, more preferably from about 0.1% to about 25%, andstill more preferably from about 0.5% to about 10%, by weight of thecomposition. The exact content (%) of humectants, emollients,moisturizers, and conditioning agents to be used in the compositionswill depend on the humectant, emollient, moisturizer, and conditioningagent utilized since such agents vary widely in potency.

Humectants are ingredients that help maintain moisture levels in skin.Humectants include, for example, polyhydric alcohols, water solublealkoxylated nonionic polymers, and mixtures thereof. Polyhydric alcoholsuseful herein include polyhdroxy alcohols aforementioned and glycerin,hexylene glycol, ethoxylated glucose, 1,2-hexane diol, dipropyleneglycol, trehalose, diglycerin, maltitol, maltose, glucose, fructose,sodium chondroitin sulfate, sodium hyaluronate, sodium adenosinephosphate, sodium lactate, pyrrolidone carbonate, glucosamine,cyclodextrin, and mixtures thereof. Water soluble alkoxylated nonionicpolymers useful herein include polyethylene glycols and polypropyleneglycols having a molecular weight of up to about 1000 such as those withCTFA names PEG-200, PEG-400, PEG-600, PEG-1000, and mixtures thereof.Additional humectants include acetyl arginine, algae extract, aloebarbadensis leaf extract, 2,3-butanediol, chitosan lauroyl glycinate,diglycereth-7 malate, diglycerin, diglycol guanidine succinate,erythritol, fructose, glucose, glycerin, honey, hydrolyzed proteins,hydroxypropyltrimonium hyaluronate, inositol, lactitol, maltitol,maltose, mannitol, mannose, methoxy polyethylene glycol,myristamidobutyl guanidine acetate, polyglyceryl sorbitol, potassiumpyrollidone carboxylic acid (PCA), propylene glycol, butylene glycol,sodium pyrollidone carboxylic acid (PCA), sorbitol, sucrose, dextransulfate (i.e., of any molecular weight), natural moisturizing factors,and/or urea.

Skin conditioners can include, but are not limited to, guanidine, urea,glycolic acid, glycolate salts (e.g., ammonium and quaternary alkylammonium), salicylic acid, lactic acid, lactate salts (e.g., ammoniumand quaternary alkyl ammonium), aloe vera in any of its variety of forms(e.g., aloe vera gel), polyhydroxy alcohols such as sorbitol, mannitol,xylitol, erythritol, hexanetriol, butanetriol, propylene glycol,butylene glycol, hexylene glycol and the like, polyethylene glycols,propoxylated glycerols, sugars (e.g., melibiose), starches, sugar andstarch derivatives (e.g., alkoxylated glucose, fructose, glucosamine),C1-C30 monoesters and polyesters of sugars and related materials,hyaluronic acid, lactamide monoethanolamine, acetamide monoethanolamine,panthenol, dexpanthenol, allantoin, and mixtures thereof. Skinconditioners can also include fatty acids, fatty acid esters, lipids,ceramides, cholesterol, cholesterol esters, bee wax, petrolatum, andmineral oil.

Emulsions can be configured to be administered and/or applied to asubject. Suitable methods of administration include, but are not limitedto, being introduced into, instilled into, implanted in, applied into,or applied onto the vulvovaginal anatomy, the rectal anatomy, the skin,or the eye in a subject. For example, in some aspects, the emulsion isconfigured to be applied into the vagina in a subject. In other aspects,the emulsion is configured to be applied onto and around the vulva in asubject.

Anatomical and physiological interactions, physiological clearance,diffusion, or any combination thereof, can lead to the release of thecell membrane fluidity enhancing agent, the fatty acid and at least oneof, the bioactive agent, the pH buffering system, the antioxidant, thetocopherol, the ceramide, the active agent, or any combination thereof,from the stable water-in-silicone emulsion, thus providing atherapeutically effective dose of to the subject.

In some embodiments, the emulsified formulation provides atherapeutically effective dose for up to 2 hours from a single dose. Insome embodiments, the emulsified formulation provides a therapeuticallyeffective dose for up to 4 hours from a single dose. In someembodiments, the emulsified formulation provides a therapeuticallyeffective dose for up to 8 hours from a single dose. In someembodiments, the emulsified formulation provides a therapeuticallyeffective dose for up to 12 hours from a single dose. In someembodiments, the emulsified formulation provides a therapeuticallyeffective dose for up to 18 hours from a single dose. In someembodiments, the emulsified formulation provides a therapeuticallyeffective dose for up to 24 hours from a single dose. In someembodiments, the emulsified formulation provides a therapeuticallyeffective dose for up to 48 hours from a single dose. In someembodiments, the emulsified formulation provides a therapeuticallyeffective dose for up to 3 days from a single dose. In some embodiments,the emulsified formulation provides a therapeutically effective dose forup to 5 days from a single dose. In some embodiments, the emulsifiedformulation provides a therapeutically effective dose for up to 7 daysfrom a single dose. In some embodiments, the emulsified formulationprovides a therapeutically effective dose for up to 14 days from asingle dose.

In embodiment, the composition can be administered as needed, such asonce daily, from two to five times daily, up to two times or up to threetimes daily, or up to eight times daily. In embodiments, the compositionis administered thrice daily, twice daily, once daily, fourteen days on(four times daily, thrice daily or twice daily, or once daily) and 7days off in a 3-week cycle, up to five or seven days on (four timesdaily, thrice daily or twice daily, or once daily) and 14-16 days off in3 week cycle, or once every two days, or once a week, or once every 2weeks, or once every 3 weeks.

In other examples, the composition is administered once a week, or onceevery two weeks, or once every 3 weeks or once every 4 weeks for atleast 1 week, in some embodiments for 1 to 4 weeks, from 2 to 6 weeks,from 2 to 8 weeks, from 2 to 10 weeks, or from 2 to 12 weeks, 2 to 16weeks, or longer (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 36, 48,or more weeks).

Pharmaceutically acceptable constituents, excipients or agents may alsobe included in the compositions described herein. In some aspects, thepharmaceutical acceptable agents may stabilize the composition, allow itto be readily administered to the vulvovaginal anatomy (e.g., the vulva,vagina, or both), the rectal anatomy, the skin, or the eye of a subject,increase its ability to provide symptom relief, treat underlyingpathophysiology or infection, or prophylactically protect the vagina ofa subject, or otherwise make the composition suitable for therapeuticuse in a subject. Accordingly, the described composition may furthercomprise a pharmaceutically acceptable excipient, as would be known toan individual skilled in the relevant art. In view of the inclusion ofactive agents in some of the described vulvovaginal, rectal,dermatological, or ophthalmic compositions, disclosed herein are alsopharmaceutical compositions having a stable water-in-silicone emulsion,an emulsifier, a cell membrane fluidity enhancing agent, a fatty acid, apreservative, and at least one of, a bioactive agent, a pH bufferingsystem, a viscosity enhancing agent, an antioxidant, a tocopherol, aceramide, and an active agent, as provided herein. The describedpharmaceutical compositions may be administered to a subject in order toprovide symptom relief, treat underlying pathophysiology or infection,or prophylactically protect the vagina of a subject.

The present disclosure also provides methods comprising combinationtherapy for the treatment or prevention of the diseases and conditionsdescribed herein. As used herein, “combination therapy” or “co-therapy”includes the administration of a composition described herein, e.g., acomposition comprising a stable water-in-silicone emulsion having acontinuous silicone phase and an aqueous phase, wherein the emulsioncomprises a sterol at a concentration from about 0.1% to about 4% byweight, of the total weight of the composition, with at least oneadditional agent, as disclosed herein, as part of a specific treatmentregimen intended to provide the beneficial effect from the co-action ofthese therapeutic compositions.

In embodiments, the at least one additional agent in combination therapymay be a therapeutic agent or a non-therapeutic agent. The beneficialeffect of the combination includes, but is not limited to,pharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic compounds and the disclosed composition. Thebeneficial effect of the combination may also relate to the mitigationof a toxicity, side effect, or adverse event associated with anotheragent in the combination. “Combination therapy” may be, but generally isnot, intended to encompass the administration of two or more of thesetherapeutic compounds as part of separate monotherapy regimens thatincidentally and arbitrarily result in the combinations of the presentdisclosure.

In the context of combination therapy, administration of thecompositions described herein, may be simultaneous with or sequential tothe administration of the one or more additional agents. In anotheraspect, administration of the different components of a combinationtherapy may be at different frequencies. The one or more additionalagents may be administered prior to (e.g., 5 minutes, 15 minutes, 30minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks,5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, orsubsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours,96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks,or 12 weeks after) the administration of a compound of the presentdisclosure.

The one or more additional agents can be formulated forco-administration with a composition of the present disclosure in asingle dosage form, as described herein. The one or more additionalagents can be administered separately from the dosage form thatcomprises the composition of the present disclosure. When the additionalagent is administered separately from a composition of the presentdisclosure, it can be by the same or a different route of administrationas the composition of the instant disclosure.

Preferably, the administration of a composition of the presentdisclosure in combination with one or more additional agents provides asynergistic response in the subject having a disorder, disease orcondition of the present disclosure. In this context, the term“synergistic” refers to the efficacy of the combination being moreeffective than the additive effects of either single therapy alone. Thesynergistic effect of combination therapy according to the disclosurecan permit the use of lower dosages and/or less frequent administrationof at least one agent in the combination compared to its dose and/orfrequency outside of the combination. The synergistic effect can bemanifested in the avoidance or reduction of adverse or unwanted sideeffects associated with the use of either therapy in the combinationalone.

“Combination therapy” also embraces the administration of thecomposition of the present disclosure in further combination withnon-drug therapies (e.g., surgery or radiation treatment). Where thecombination therapy further comprises a non-drug treatment, the non-drugtreatment may be conducted at any suitable time so long as a beneficialeffect from the co-action of the combination of the therapeuticcompounds and non-drug treatment is achieved.

Physical and Chemical Properties of the Water-in-Silicone EmulsionDroplet Size

In some examples, the emulsion described herein comprises droplets(alternatively, “particles”). The liquid-liquid droplets comprising theemulsified formulation can have a median diameter of up to 250 microns.For example, the droplets can have a median diameter from about 10 toabout 250 microns, from about 50 to 250 microns, from about 100 to 250microns, from about 150 to 250 microns, or from about 200 to 250microns. In some examples, the droplet/particle is about 10 to about100,000 nanometers (100 μm) in diameter. For example, thedroplet/particle may be about 10, 50, 100, 200, 300, 400, 500, 1000,10,000, or 100,000 nanometers in diameter. In some embodiments, a deviceor apparatus may be used to deliver a droplet/particle to the subject.

The droplet size may be analyzed by known methods in the art. Suitablemethods of droplet size analysis include, but are not limited to, lightmicroscopy, dynamic light scattering, and laser diffraction.

Methods of Preparing

Also provided herein are methods of preparing the compositionscomprising a water-in-oil emulsion. In some examples, the emulsion canbe prepared using techniques including, but are not limited to,rotor-stator emulsification, static mixing, or high shear mixing.

In embodiments, the composition is emulsified to form a stable emulsionwith the desired droplet size. High-shear devices that may be usedinclude, but are not limited, to IKA Ultra-Turrax disperser, IKADispax-Reactor DR and DRS (Dispax-Reactor shear mixers include the DR3-6with three stages of rotor/stator combinations and the tip speed of therotor/stator generators may be varied by a variable frequency drive thatcontrols the motor), Silverson mixer (a two-stage mixer, whichincorporates a rotor/stator design and has high-volume pumpingcharacteristics similar to centrifugal pump), inline shear mixers bySilverson Corporation (a rotor-stator emulsification approach), jetmixers (venturi-style/cavitation shear mixers), Ultrasonolator by theSonic Corporation (ultrasonic emulsification approach), microfluidizershear mixers available by Microfluidics Inc (high-pressurehomogenization shear mixers), ultrasonic mixers, and any other availablehigh-shear mixer.

In other embodiments, the composition is emulsified to form a stableemulsion using a static mixer. A static mixer is a precision engineereddevice for the continuous mixing of fluid materials, without movingcomponents.

Composition, Generally

As described herein, certain aspects of the present invention relate tothe use of the compositions to make cosmetics, personal care products,feminine care products, hygiene products, dermatology products,ophthalmic products, pharmaceutical preparations, or medicaments formaintaining healthy skin, skin rejuvenation, restoration of damaged skinincluding, but not limited to, skin after cosmetic and dermatologicalprocedures, wound healing, treatment of atrophy of any human tissueincluding vulvovaginal atrophy, and/or other conditions, disorders anddiseases of skin and mucosa in humans associated with changes inextracellular matrix components.

This is accomplished by topical application of the composition of theinvention to the skin or mucosa of the human needing such treatment. Insome limited cases, this can be accomplished by topical administrationof the composition of the invention in a human needing such treatment.

Certain aspects of the present invention also relate to methods of usingsuch compositions for the treatment or prevention in dermatologicalapplications, as well as for enhancing wound healing, reducing theatrophy of any human tissue including vulvovaginal atrophy, and forimproving other conditions, disorders and diseases of skin and mucosa inhumans. These methods generally involve topically applying thecomposition to the affected skin or the affected anatomy when needed, inthe amount and at the frequency best suited for the purpose. Methods ofpreventing, delaying the onset, or treating a skin or mucosal condition,disorder or disease are also contemplated.

Those skilled in the art will further recognize that the administrationof any of the compositions and/or formulations of the invention treats,alleviates, or ameliorates conditions, disorders and diseases of skinand mucosa in humans, for example wounded skin, damaged skin aftercosmetic and dermatological procedures, atrophy of skin and mucosa dueto other causes than aging (e.g., emotional stress, use of oralcontraceptive pills, use of aromatase inhibitors, due to surgery, etc.),and for other conditions, and/or disorders and diseases of skin andmucosa in humans.

Vulvovaginal Compositions

Vulvar and vaginal atrophy (VVA), resulting from the loss of estrogenstimulation on vaginal and vulvar tissue, is a common medical conditionin peri- and post-menopausal women. VVA often manifests with discomfortwhat can be experienced as vaginal dryness, lack of lubrication,rawness, burning, irritation, inflammation, atrophic vaginitis,dyspareunia (pain during sexual intercourse), and pain generally. VVAoccurs most often after menopause, but it can also develop duringbreast-feeding, as a consequence of breast cancer treatment, or at anyother time the women's estrogen production declines. Furthermore, recentevidence indicates that women taking oral contraceptives (which cancause a decline in the production of certain sex hormones such astestosterone) may also experience vulvovaginal atrophy. VVA will occurin most post-menopausal women at some point in their lives. There are anestimated 64 million post-menopausal women in the United States, and asmany as 32 million women may suffer from VVA symptoms.

Existing non-prescription treatments (e.g., non-hormonal,over-the-counter (OTC) creams, moisturizers, and lubricants) are lackingin several areas, for example, they are not capable of restoring stasisto the anatomy and physiology; they often contain ingredients that arenot well-tolerated in the vaginal canal; they are often not isotonic;and they are dramatically inferior to Hormone Replacement Therapies(HRT) in terms of symptom relief and treatment of underlying pathology.

The pathophysiology of VVA is such that the decreasing levels ofestrogen associated with peri- and post-menopause cause (1) a thinningof the superficial cells and stratified squamous epithelial cells thatline the vaginal mucosa and (2) a decrease in squamous epithelialglycogenation, resulting in a decrease of exfoliated, glycogenatedcells. Glycogen is an important biomolecule that is responsible formaintaining vaginal health. The conversion of glycogen to lactic acid byLactobacilli, the beneficial flora of the vaginal mucosa, is essentialfor maintaining the healthy, low vaginal pH. In the absence of glycogen,the vaginal pH rises, resulting in a decrease in Lactobacilli and apotential for overgrowth of harmful bacteria that can lead to infectionand inflammation. Further, the decline in estrogen levels leads todecreased vulvovaginal blood flow, decrease mucous production, anddecreased vaginal lubrication. Thus, provided herein are compositionsand methods that address these needs. Provided herein are vulvovaginalcompositions (e.g., lubricants, moisturizers, creams) that arenon-hormonal, isotonic, long-lasting, capable of slowing the progressionof VVA (e.g. by restoring pH balance, providing meaningful lubrication,and providing symptom relief—vaginal dryness—for at least 24 hours froma single application), and comprise only well-tolerated, generallyrecognized as safe (GRAS) ingredients that are latex and lactobacillicompatible.

Provided herein are compositions, e.g., vulvovaginal compositions. Insome embodiments, the vulvovaginal compositions are formulatedspecifically to not require active agents for the treatment of certainindication. Alternatively, the present disclosure also providesvulvovaginal compositions that are formulated to enable incorporation ofactive agents. In both cases, the formulation method is selectedspecifically to exert control over 1) formulation stability, 2)mechanical properties, and 3) therapeutically relevant incorporation ofdesired constituents, excipients, or agents.

The disclosed vulvovaginal compositions can be administered byapplication. For example, the vulvovaginal compositions can be appliedinto the vagina using an applicator known by those skilled in the art.Additionally, the vulvovaginal compositions can be applied onto thevulva by methods known by those skilled in the art. In some embodiments,the vulvovaginal composition can be administered into the vagina. Insome aspects, the vulvovaginal composition can be applied into thevagina. In other embodiments, the vulvovaginal composition can beadministered onto or around the vulva. In some aspects, the vulvovaginalcomposition can be applied onto or around the vulva. In otherembodiments, the vulvovaginal composition can be administered onto oraround vaginal superficial cells. In some aspects, the vulvovaginalcomposition can be applied onto or around vaginal superficial cells. Inyet other embodiments, the vulvovaginal composition can be administeredonto or around vaginal squamous epithelial cells. In some aspects, thevulvovaginal composition can be applied onto or around vaginal squamousepithelial cells.

The disclosed vulvovaginal compositions can be used to provide vaginalsymptom relief, treat underlying pathophysiology or infection of thevaginal anatomy, or prophylactically protect the vagina in a subject by,for example, administering the composition into the vagina. Thedisclosed vulvovaginal compositions can be used to provide vulvarsymptom relief, treat underlying pathophysiology or infection of thevulvar anatomy, or prophylactically protect the vulva in a subject by,for example, administering the composition onto the vulva.

In embodiments, the vulvovaginal composition can be used to prevent ortreat bacterial vaginosis, vulvovaginal atrophy, yeast infections, assexually transmitted infection (STI) and/or sexually transmitted disease(STD) prophylaxis, as a personal lubricant, a vaginal moisturizer, alocal hormone replacement therapy, or as contraception.

Additionally, the disclosed compositions can be used to providevulvovaginal symptom relief, treat underlying pathophysiology orinfection of the vulvovaginal anatomy, or prophylactically protect thevulvovaginal anatomy in a subject. The need for treatment or prophylaxiscan arise from a number of conditions, including, but not limited to,menopause, peri-menopause, post-menopause, decrease in estrogenconcentration, atrophic vaginitis, vulvar and vaginal atrophy, bacterialvaginosis, vaginal dryness, vaginal itch, vaginal irritation,dyspareunia, bacterial infection, yeast infection, urinary tractinfection, need for vaginal lubrication and moisture, sexualintercourse, need for contraceptive prophylaxis, or any combinationthereof.

In some examples, the disclosed vulvovaginal compositions can include abioactive agent. Examples of contemplated bioactive agents include, butare not limited to, glycogen, lactic acid, cholesterol, or anycombination thereof.

In some examples, the disclosed vulvovaginal compositions can include anactive agent. Examples of contemplated active agents include, but arenot limited to, antifungals, antibiotics, spermicides, estrogens,estrogen derivatives, progesterone, progesterone derivatives, estrogenprecursors, steroids, anti-inflammatories, antivirals/antiretrovirals(e.g. CCR5 antagonists, nucleoside reverse transcriptase inhibitors(NRTIs) as described herein), non-nucleoside reverse transcriptaseinhibitors (NNRTIs), protease inhibitors (PIs) (e.g., atazanavir(Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir(Crixivan), lopinavir/ritonavir (Kaletra), nelfinavir (Viracept),ritonavir (Norvir), saquinavir (Invirase), tipranavir (Aptivus),atazanavir/cobicistat (Evotaz), and darunavir/cobicistat (Prezcobix)),fusion inhibitors (e.g., T-20 (enfuvirtide, Fuzeon)), integraseinhibitors e.g., raltegravir, dolutegravir, and cabotegravir),post-attachment inhibitors, and pharmacokinetic enhancers.

In embodiments the active agent for the vulvovaginal composition caninclude a steroidal anti-inflammatory agent. Exemplary steroidalanti-inflammatory bioactive agents include, but are not limited to,corticosteroids such as prasterone, hydrocortisone,hydroxyltriamcinolone, alpha-methyl dexamethasone,dexamethasone-phosphate, beclomethasone dipropionate, clobetasolvalerate, desonide, desoxymethasone, desoxycorticosterone acetate,dexamethasone, dichlorisone, diflorasone diacetate, diflucortolonevalerate, fluadrenolone, fluclorolone acetonide, fludrocortisone,flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortinebutylester, fluocortolone, fluprednidene (fluprednylidene) acetate,flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisonebutyrate, methylprednisolone, triamcinolone acetonide, cortisone,cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate,fluradrenolone acetonide, medrysone, amcinafel, amcinafide,betamethasone and the balance of its esters, chloroprednisone,chloroprednisone acetate, clocortelone, clescinolone, dichlorisone,difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone,fluprednisolone, hydrocortisone valerate, hydrocortisonecyclopentylpropionate, hydrocortamate, meprednisone, paramethasone,prednisolone, prednisone, beclomethasone dipropionate, triamcinolone,and mixtures thereof may be used.

In other embodiments, the active agent comprises a second class ofanti-inflammatory agents which is useful in the compositions, andincludes the nonsteroidal anti-inflammatory agents. The variety ofcompounds encompassed by this group are well-known to those skilled inthe art.

In one embodiment, the additional agent is an anti-viral agent.Non-limiting examples of anti-viral agents that may be used incombination with a composition as described herein include Acemannan;Acyclovir; Acyclovir Sodium; Adefovir; Alovudine; Alvircept Sudotox;Amantadine Hydrochloride; Aranotin; Arildone; Atevirdine Mesylate;Avridine; Cidofovir; Cipamfylline; Cytarabine Hydrochloride; DelavirdineMesylate; Desciclovir; Didanosine; Disoxaril; Edoxudine; Enviradene;Enviroxime; Famciclovir; Famotine Hydrochloride; Fiacitabine;Fialuridine; Fosarilate; Foscarnet Sodium; Fosfonet Sodium; Ganciclovir;Ganciclovir Sodium; Idoxuridine; Kethoxal; Lamivudine; Lobucavir;Memotine Hydrochloride; Methisazone; Nevirapine; Penciclovir; Pirodavir;Ribavirin; Rimantadine Hydrochloride; Saquinavir Mesylate; SomantadineHydrochloride; Sorivudine; Statolon; Stavudine; Tilorone Hydrochloride;Trifluridine; Valacyclovir Hydrochloride; Vidarabine; VidarabinePhosphate; Vidarabine Sodium Phosphate; Viroxime; Zalcitabine;Zidovudine; and Zinviroxime. Combinations of anti-viral agents are alsocontemplated in the compositions described herein.

In some embodiments, the vulvovaginal composition includes one or moreactive and/or bioactive agents. In some embodiments, the vulvovaginalcomposition includes two active agents, for example, estradiol andprasterone. In another example, the vulvovaginal composition includes anactive and a bioactive agent, for example, estradiol and glycogen,respectively.

In embodiments, the vulvovaginal composition includes an active agentfrom about 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the vulvovaginal composition includes a bioactive agentfrom about 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the present disclosure includes a vulvovaginalcomposition including a cell membrane fluidity enhancing agent (e.g., asterol, wherein exemplary sterols include cholesterol, cholesterolderivatives, phytosterols, or any combination thereof) and apreservative. Examples of preservatives include an anti-microbialpreservative, for example, benzalkonium chloride, thimerosal,chlorhexidine, chlorobutanol, methyl paraben, propyl paraben,phenylethyl alcohol, edetate disodium, sorbic acid, benzoic acid, cetylbromide, cetyl pyridinium chloride, benzyl bromide, EDTA, phenylmercurynitrate, phenylmercury acetate, thimerosal, merthiolate, acetate andphenylmercury borate, polymyxin B sulphate, methyl and propyl parabens,quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodiumproprionate, and sodium perborate, or any combination(s) thereof.

In embodiments the preservatives may be used in any suitable amounts.For example, the preservative may be used in an amount about 0.001% byweight-1.0% by weight based on the total weight of composition.

In embodiments, the vulvovaginal composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a pH of about 3 to about 4.5. In otherembodiments, the pH is about 3.8.

In some examples, the vulvovaginal composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has an osmolarity of about 280 to about 380mOsm/kg.

The vulvovaginal composition should have a zero-rate viscosity that isresistant change over time and/or temperature. The terms “viscous,”“viscosity”, “zero-rate viscosity’ and the like refer herein, in theusual and customary sense, to a measure of the resistance of a materialto deformation (e.g., liquid behavior) upon application of a force(e.g., shear stress or tensile stress). The viscosity of the emulsionscan also depend on the temperature, along with several other effects,such as shear rate, average droplet size, and droplet size distribution.As described herein, the viscosity may typically mean that thevulvovaginal composition has a zero-rate viscosity of about 50 kPa-s toabout 1000 kPa-s at 25° C. In examples, the composition has the desiredzero-rate viscosity, (e.g., about 200 kPas at 25° C.) for at least 12months.

In some examples, the vulvovaginal composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a zero-rate viscosity of about 50 kPa-s toabout 1000 kPa-s at 25° C.

In some examples, the vulvovaginal composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has rheological properties that have negligiblevariation with temperature between 25° C. and 37° C.

Vulvovaginal Methods

Also provided herein are methods for providing vulvovaginal symptomrelief, treating underlying pathophysiology or infection of thevulvovaginal anatomy, or prophylactically protecting the vulvovaginalanatomy in a subject comprising administering to a subject any one ofthe compositions disclosed herein. In some embodiments, the methods forproviding vulvovaginal symptom relief, treating underlyingpathophysiology or infection of the vulvovaginal anatomy, orprophylactically protecting the vulvovaginal anatomy in a subject cancomprise administering to a subject a vulvovaginal compositioncomprising a stable water-in-silicone emulsion, an emulsifier, a cellmembrane fluidity enhancing agent, a fatty acid, a preservative, and atleast one of, a bioactive agent, a pH buffering system, a viscosityenhancing agent, an antioxidant, a tocopherol, and an active agent. Inother embodiments, the methods for providing vulvovaginal symptomrelief, treating underlying pathophysiology or infection of thevulvovaginal anatomy, or prophylactically protecting the vulvovaginalanatomy in a subject can comprise administering to a subject avulvovaginal composition consisting of a stable water-in-siliconeemulsion, an emulsifier, a cell membrane fluidity enhancing agent, afatty acid, a preservative, and at least one of, a bioactive agent, a pHbuffering system, a viscosity enhancing agent, an antioxidant, atocopherol, and an active agent. In yet other embodiments, the methodsfor providing vulvovaginal symptom relief, treating underlyingpathophysiology or infection of the vulvovaginal anatomy, orprophylactically protecting the vulvovaginal anatomy in a subject cancomprise administering to a subject a vulvovaginal compositionconsisting essentially of a stable water-in-silicone emulsion, anemulsifier, a cell membrane fluidity enhancing agent, a fatty acid, apreservative, and at least one of, a bioactive agent, a pH bufferingsystem, a viscosity enhancing agent, an antioxidant, a tocopherol, andan active agent.

Dermatological Compositions

Also provided herein are dermatological compositions. The dermatologicalcompositions described herein can be used as a skin protectant ormoisturizer. In other examples, the dermatological compositions can beused to treat or prevent eczema, psoriasis, plaque psoriasis, dry skin,chaffed skin, diaper rash, skin rash, hives, poison ivy, skin pain,post-herpetic neuralgia, burns, wound healing, skin infections,dermatitis, atopic dermatitis, acne, impetigo, melanoma, rosacea,chapped skin, chapped lips, or skin wrinkles. In some embodiments, thedermatological compositions can be formulated as cosmetics, skinlotions, skin moisturizers, or skin creams.

In some examples, the disclosed dermatological compositions can includea bioactive agent. Examples of contemplated bioactive agents include,but are not limited to, hyaluronic acid, cholesterol, or any combinationthereof.

In some examples, the disclosed dermatological composition can includean active agent. Exemplary active agents contemplated, include but arenot limited to, antibiotics, antimicrobials, antifungals, antiseptics,local anesthetics, analgesics, anti-inflammatories, immunosuppressants,steroids, corticosteroids, calcineurin inhibitors, PDE4 inhibitors,salicylic acid, retinoids, antihistamines, benzoyl peroxide, andnanocrystalline silver.

Exemplary antibiotics include, but are not limited to amoxicillin,doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole,azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanate,and levofloxacin. Additional antibiotcs include Mikacin, Gentamicin,Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin,Spectinomycin(Bs), Geldanamycin, Herbimycin, Rifaximin, Loracarbef,Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem, Cefadroxil,Cefazolin, Cephradine, Cephapirin, Cephalothin, Cefalexin, Cefaclor,Cefoxitin Cefotetan, Cefamandole, Roxithromycin, Telithromycin,Spiramycin, Fidaxomicin, Furazolidone, Nitrofurantoin(Bs), Linezolid,Posizoli, Radezolid, Torezolid, Ampicillin, Azlocillin, Dicloxacillin,Flucloxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin,Penicillin G, Penicillin V, Piperacillin, Penicillin G, Temocillin,Ticarcillin, Ampicillin/sulbactam, Piperacillin/tazobactam,Ticarcillin/clavulanate, Bacitracin, Colistin, Polymyxin B,Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin,Norfloxacin, Ofloxacin, Trovafloxacin, Minocycline, Oxytetracycline,Tetracycline, Clofazimine, Dapsone, Capreomycin, CycloserinemPyrazinamide, Rifampicin, Rifabutin, Rifapentine, Streptomycin,Metronidazole, and Mupirocin

Exemplary antimicrobials include, but are not limited to amoxicillin,doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole,azithromycin, sulfamethoxazole/trimethoprim, amoxicillin/clavulanate,and levofloxacin.

Exemplary antifungals include, but are not limited to, miconazole,clotrimazole, amphotericin B, ketoconazole, fluconazole, isavuconazole,itraconazole, posaconazole, voriconazole, anidulafungin, caspofungin,micafungin, and flucytosine.

Exemplary antiseptics include ethanol, sodium hypochlorite,chlorhexidine, hexachlorophene, povidone iodine, sodium hypochlorite,sodium hypochlorite, benzethonium chloride, triclosan, oxychlorosenesodium, benzalkonium chloride, and silver nitrate.

Exemplary local anesthetics include amylocaine, ambucaine, articaine,benzocaine, benzonatate, bupivacaine, butacaine, butanilicaine,chloroprocaine, cinchocaine(INN), cocaine, cyclomethycaine, dibucaine,diperodon, dimethocaine, eucaine, etidocaine, hexylcaine, fomocaine,fotocaine, hydroxyprocaine, isobucaine, levobupivacaine, lidocaine(lignocaine), mepivacaine, meprylcaine, metabutoxycaine, nitracaine,orthocaine, oxetacaine(oxethazaine), oxybuprocaine, paraethoxycaine,phenacaine, piperocaine, piridocain, pramocaine, prilocaine, primacaine,procaine, procainamide, proparacaine, propoxycaine, pyrrocaine,quinisocaine(INN), ropivacaine, trimecaine, tetracaine, tolycaine, andtropacocaine.

Exemplary analgesics include codeine, fentanyl, hydrocodone (Hysingla,Zohydro, Hydrocodone/acetaminophen (Lorcet, Lortab, Norco, Vicodin),Hydromorphone (Dilaudid, Exalgo), Meperidine (Demerol), Methadone(Dolophine, Methadose), Morphine (Kadian, MS Contin, Morphabond),Oxycodone (OxyContin, Oxaydo), Oxycodone and acetaminophen (Percocet,Roxicet), and Oxycodone and naloxone.

Exemplary anti-inflammatories include celecoxib (Celebrex), diclofenac(Cambia, Cataflam, Voltaren-XR, Zipsor, Zorvolex), diflunisal (Dolobid),etodolac (Lodine), ibuprofen (Motrin, Advil), indomethacin (Indocin),ketoprofen (Active-Ketoprofen, ketorolac, nabumetone naproxen (Aleve,Anaprox, Naprelan, Naprosyn), oxaprozin (Daypro), piroxicam (Feldene),salsalate, sulindac, and tolmetin.

Exemplary immunosuppressants include corticosteroids (e.g., prednisone(Deltasone, Orasone), budesonide (Entocort EC), prednisolone, and(Millipred)), Janus kinase inhibitors (e.g. tofacitinib (Xeljanz)),Calcineurin inhibitors, e.g., cyclosporine (Neoral, Sandimmune,SangCya), and tacrolimus (Astagraf XL, Envarsus XR, Prograf), mTORinhibitors, e.g., sirolimus (Rapamune), and everolimus (Afinitor,Zortress), IMDH inhibitors, e.g., azathioprine (Azasan, Imuran),leflunomide (Arava), and mycophenolate (CellCept, Myfortic), biologics,e.g., abatacept (Orencia), adalimumab (Humira), anakinra (Kineret),certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi),infliximab (Remicade), ixekizumab (Taltz), natalizumab (Tysabri),rituximab (Rituxan), secukinumab (Cosentyx), tocilizumab (Actemra),ustekinumab (Stelara), vedolizumab (Entyvio), and monoclonal antibodies,e.g., basiliximab (Simulect), daclizumab (Zinbryta), and muromonab(Orthoclone OKT3).

Exemplary calcineurin inhibitors include astagraf XL, cyclosporine,cyclosporine ophthalmic, Elidel, Envarsus XR, Gengraf, Hecoria, Neoral,pimecrolimus, Prograf, Protopic, Restasis, Sandimmune, tacrolimus, andtacrolimus ointment.

Exemplary phosphodiesterase 4 (PDE4) inhibitors include Adibendan,Aminophylline, Aminophylline dehydrate, Amipizone, Apremilast,Arofylline, Atizoram, Befuraline, Bemarinone hydrochloride, Bemoradan,Benafentrine, Bucladesine, Buflomedil, Buquineran, CC-1088, Carbazeran,Catramilast, Cilomilast, Cilostamide, Cilostazol, Cipamfylline,Crisaborole, Daxalipram, Denbufylline, Dimabefylline, Diniprofylline,Dipyridamole, Doxofylline, Drotaverine, Dyphylline, Enoximone,Etamiphyllin, Etofylline, Filaminast, Flufylline, Fluprofylline,Furafylline, Imazodan, Imazodan hydrochloride, Inamrinone, Inamrinonelactate, Isbufylline, Lirimilast, Lisofylline, Lomifylline, Medorinone,Metescufylline, Midaxifylline, Milrinone, Milrinone lactate, Motapizone,Nanterinone, Nestifylline, Nitraquazone, Oglemilast, Oglemilast Sodium,Olprinone, Oxagrelate, Oxtriphylline, Papaverine, Papaverinehydrochloride, Papaverine sulfate, Parogrelil, Pelrinone hydrochloride,Pentifylline, Pentoxifylline, Perbufylline, Piclamilast, Pimefylline,Pimobendan, Piroximone, Prinoxodan, Proxyphylline, Pumafentrine,Quazinone, Quazodine, Revamilast, Revizinone, Roflumilast, Rolipram,Ronomilast, Saterinone, Senazodan, Siguazodan, Tetomilast, Tofimilast,Trapidil, Vesnarinone, and Zardaverine

In some embodiments, the dermatological composition includes one or moreactive and/or bioactive agents. In some embodiments, the dermatologicalcomposition includes two active agents, for example, lidocaine andclindamycin. In another example, the dermatological composition includesan active and a bioactive agent, for example, retinol and hyaluronicacid, respectively.

In embodiments, the dermatological composition includes an active agentfrom about 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the dermatological composition includes a bioactiveagent from about 0.0001 percent by weight to about 90 percent by weightof the composition, from about 0.0001 percent by weight to about 1percent by weight, from about 0.0001 percent by weight to about 10percent by weight, from about 0.0001 percent by weight to about 20percent by weight, from about 0.0001 percent by weight to about 30percent by weight, from about 0.0001 percent by weight to about 40percent by weight, from about 0.0001 percent by weight to about 50percent by weight, from about 0.0001 percent by weight to about 60percent by weight, from about 0.0001 percent by weight to about 70percent by weight, from about 0.0001 percent by weight to about 80percent by weight, from about 0.001 percent by weight to about 90percent by weight of the composition, from about 0.001 percent by weightto about 1 percent by weight, from about 0.001 percent by weight toabout 10 percent by weight, from about 0.001 percent by weight to about20 percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the present disclosure includes a dermatologicalcomposition including a cell membrane fluidity enhancing agent (e.g., asterol, wherein exemplary sterols include cholesterol, cholesterolderivatives, phytosterols, or any combination thereof) and apreservative. Examples of preservatives include an anti-microbialpreservative, for example, benzalkonium chloride, thimerosal,chlorhexidine, chlorobutanol, methyl paraben, propyl paraben,phenylethyl alcohol, edetate disodium, sorbic acid, benzoic acid, cetylbromide, cetyl pyridinium chloride, benzyl bromide, EDTA, phenylmercurynitrate, phenylmercury acetate, thimerosal, merthiolate, acetate andphenylmercury borate, polymyxin B sulphate, methyl and propyl parabens,quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodiumproprionate, and sodium perborate, or any combination(s) thereof.

In embodiments the preservatives may be used in any suitable amounts.For example, the preservative may be used in an amount about 0.001% byweight-1.0% by weight based on the total weight of composition.

In embodiments, the dermatological composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a pH of about 4.5 to about 6.5. In otherembodiments, the pH is about 5.5.

In some examples, the dermatological composition including a cellmembrane fluidity enhancing agent (e.g., a sterol, wherein exemplarysterols include cholesterol, cholesterol derivatives, phytosterols, orany combination thereof) has an osmolarity of about 200 to about 500mOsm/kg.

The dermatological composition should have a zero-rate viscosity that isresistant change over time and/or temperature. The terms “viscous,”“viscosity,” “zero-rate viscosity” and the like refer herein, in theusual and customary sense, to a measure of the resistance of a materialto deformation (e.g., liquid behavior) upon application of a force(e.g., shear stress or tensile stress). The viscosity of the emulsionscan also depend on the temperature, along with several other effects,such as shear rate, average droplet size, and droplet size distribution.As described herein, the viscosity may typically mean that thedermatological composition has a zero-rate viscosity of about 100 Pa-sto about 1000 kPa-s at 25° C.

In some examples, the dermatological composition including a cellmembrane fluidity enhancing agent (e.g., a sterol, wherein exemplarysterols include cholesterol, cholesterol derivatives, phytosterols, orany combination thereof) has a zero-rate viscosity of about 100 Pa-s toabout 1000 kPa-s at 25° C.

In some examples, the dermatological composition including a cellmembrane fluidity enhancing agent (e.g., a sterol, wherein exemplarysterols include cholesterol, cholesterol derivatives, phytosterols, orany combination thereof) has rheological properties that have negligiblevariation with temperature between 25° C. and 37° C.

As described herein, an exemplary dermatological composition comprisesceramide.

Dermatological Methods

Also provided herein are methods for providing dermatological symptomrelief, treating underlying pathophysiology or infection, orprophylactically protecting a subject comprising administering to asubject any one of the compositions disclosed herein.

In some embodiments, the methods for dermatological utility comprisestreating or preventing conditions including, but not limited to eczema,psoriasis, plaque psoriasis, dry skin, chaffed skin, diaper rash, skinrash, hives, poison ivy, skin pain, post-herpetic neuralgia, burns,wound protection and/or healing, skin infections, dermatitis, atopicdermatitis, acne, impetigo, melanoma, rosacea, chapped skin, chappedlips, or skin wrinkles. In other exemplary embodiments, thedermatological utility of the disclosed compositions provides that thecompositions can be formulated as cosmetics, skin lotions, skinmoisturizers, skin creams, or skin protectants.

Rectal Compositions

Also provided herein are rectal compositions. For example, thecompositions can be used to treat or prevent hemorrhoids or analfissures.

In some examples, the disclosed rectal compositions can include anactive agent. Exemplary contemplated active agents include, but are notlimited to vasoconstrictors, anti-inflammatories, steroids, localanesthetics, alpha-adrenergic receptor agonists, onabotulinumtoxin A,calcium channel inhibitors, and nitrates.

In some embodiments, the rectal composition includes one or more activeagents. In some embodiments, the rectal composition includes two activeagents, for example, lidocaine and hydrocortisone.

In embodiments, the rectal composition includes an active agent fromabout 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the rectal composition includes a bioactive agent fromabout 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the present disclosure includes a rectal compositionincluding a cell membrane fluidity enhancing agent (e.g., a sterol,wherein exemplary sterols include cholesterol, cholesterol derivatives,phytosterols, or any combination thereof) and a preservative. Examplesof preservatives include an anti-microbial preservative, for example,benzalkonium chloride, thimerosal, chlorhexidine, chlorobutanol, methylparaben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbicacid, benzoic acid, cetyl bromide, cetyl pyridinium chloride, benzylbromide, EDTA, phenylmercury nitrate, phenylmercury acetate, thimerosal,merthiolate, acetate and phenylmercury borate, polymyxin B sulphate,methyl and propyl parabens, quaternary ammonium chloride, sodiumbenzoate, potassium sorbate, sodium proprionate, and sodium perborate,or any combination(s) thereof.

In embodiments the preservatives may be used in any suitable amounts.For example, the preservative may be used in an amount about 0.001% byweight-1.0% by weight based on the total weight of composition.

In embodiments, the rectal composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a pH of about 7 to about 8. In otherembodiments, the pH is about 7.4.

In some examples, the rectal composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has an osmolarity of about 200 to about 500mOsm/kg.

The rectal composition should have a zero-rate viscosity that isresistant change over time and/or temperature. The terms “viscous,”“viscosity”, “zero-rate viscosity’ and the like refer herein, in theusual and customary sense, to a measure of the resistance of a materialto deformation (e.g., liquid behavior) upon application of a force(e.g., shear stress or tensile stress). The viscosity of the emulsionscan also depend on the temperature, along with several other effects,such as shear rate, average droplet size, and droplet size distribution.As described herein, the viscosity may typically mean that the rectalcomposition has a zero-rate viscosity of about 50 kPa-s to about 1000kPa-s at 25° C.

In some examples, the rectal composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a zero-rate viscosity of about 50 kPa-s toabout 1000 kPa-s at 25° C.

In some examples, the rectal composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has rheological properties that have negligiblevariation with temperature between 25° C. and 37° C.

Rectal Methods

Also provided herein are methods for providing rectal symptom relief ortreating underlying pathophysiology or infection in a subject comprisingadministering to a subject any one of the compositions disclosed herein.

In some embodiments, the methods for rectal utility comprises treatingconditions including, but not limited to, hemorrhoids or anal fissures.

Sunscreen Compositions

Also provided herein are sunscreen compositions. For example, thecompositions can be used to treat or prevent sun damage (e.g., damagefrom ultraviolet radiation). Regulation of skin darkening resulting fromexposure to ultraviolent light can be achieved by using the compositionsdescribed herein. Useful sunblocks include, for example, zinc oxide andtitanium dioxide. Ultraviolet light is a predominant cause of skindarkening.

In embodiments, the sunscreen compositions can include an active agent.Exemplary active agents (e.g. UV-absorbing agents) in the sunscreencompositions described herein include, but are not limited to, zincoxide, titanium dioxide, oxybenzone, avobenzone, octisalate,octocrylene, homosalate octinoxate, and para-aminobenzoic acid (e.g.,PABA).

In some embodiments, the sunscreen composition includes one or moreactive agents capable of absorbing UV-radiation. In some embodiments,the sunscreen composition includes two active agents, for example, zincoxide and oxybenzone.

In embodiments, the sunscreen composition includes an active agent fromabout 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the sunscreen composition includes a bioactive agentfrom about 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the present disclosure includes a sunscreen compositionincluding a cell membrane fluidity enhancing agent (e.g., a sterol,wherein exemplary sterols include cholesterol, cholesterol derivatives,phytosterols, or any combination thereof) and a preservative. Examplesof preservatives include an anti-microbial preservative, for example,benzalkonium chloride, thimerosal, chlorhexidine, chlorobutanol, methylparaben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbicacid, benzoic acid, cetyl bromide, cetyl pyridinium chloride, benzylbromide, EDTA, phenylmercury nitrate, phenylmercury acetate, thimerosal,merthiolate, acetate and phenylmercury borate, polymyxin B sulphate,methyl and propyl parabens, quaternary ammonium chloride, sodiumbenzoate, potassium sorbate, sodium proprionate, and sodium perborate,or any combination(s) thereof.

In embodiments the preservatives may be used in any suitable amounts.For example, the preservative may be used in an amount about 0.001% byweight-1.0% by weight based on the total weight of composition.

In embodiments, the sunscreen composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a pH of about 4.5 to about 6.5. In otherembodiments, the pH is about 5.5.

In some examples, the sunscreen composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has an osmolarity of about 200 to about 500mOsm/kg.

The sunscreen composition should have a zero-rate viscosity that isresistant change over time and/or temperature. The terms “viscous,”“viscosity”, “zero-rate viscosity’ and the like refer herein, in theusual and customary sense, to a measure of the resistance of a materialto deformation (e.g., liquid behavior) upon application of a force(e.g., shear stress or tensile stress). The viscosity of the emulsionscan also depend on the temperature, along with several other effects,such as shear rate, average droplet size, and droplet size distribution.As described herein, the viscosity may typically mean that the sunscreencomposition has a zero-rate viscosity of about 100 Pa-s to about 1000kPa-s at 25° C.

In some examples, the sunscreen composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a zero-rate viscosity of about 100 Pa-s toabout 1000 kPa-s at 25° C.

In some examples, the sunscreen composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has rheological properties that have negligiblevariation with temperature between 25° C. and 37° C.

Sunscreen Methods

Also provided herein are methods for prophylactically protecting asubject from UV damage comprising administering to a subject any one ofthe compositions disclosed herein.

In some embodiments, the methods for sunscreen utility comprisestreating or preventing conditions including, UV damage (e.g., sundamage) in a subject. For purposes as described herein, the compositionscan be used to protect or treat against a UVA and/or UVB exposure.

Transdermal Drug Delivery Compositions

Also provided herein are transdermal drug delivery compositions.Transdermal drug delivery works well for high potency drugs (e.g. oraldosage of less than 10 mg) used to treat sub-chronic and chronicindications. Transdermal drug delivery offers a desirable route ofadministration, as it avoids first-pass, hepatic circulation andclearance. For example, the compositions can be used to treat or preventpain, diabetes, neurological diseases or disorders, hormone deficiency,or nausea.

In some examples, the disclosed transdermal drug delivery compositionscan include a bioactive agent. Examples of contemplated bioactive agentsinclude, but are not limited to, serine proteases, chemical penetrationenhancers, cholesterol, or any combination thereof.

In some examples, the disclosed transdermal drug delivery compositioncan include an active agent. Exemplary active agents contemplated,include but are not limited to, analgesics, local anesthetics, hormones,steroids, sulfonylureas, alpha-glucosidase inhibitors,thiazolidinediones, glucagon-like peptide-1 (GLP-1) agonists, dipeptidylpeptidase 4 (DDP-4) inhibitors, insulins, selective sodium-glucosetransporter-2 (SGLT-2) inhibitors, antidepressants, anticonvuslants,antipsychotics, antiparkinsons, and antiemetics.

In some embodiments, the transdermal drug delivery composition includesone or more active and/or bioactive agents. In some embodiments, thetransdermal drug delivery composition includes two active agents, forexample, estrogen and progesterone. In another example, the transdermaldrug delivery composition includes an active and a bioactive agent, forexample, testosterone and serine protease, respectively.

In embodiments, the transdermal drug delivery composition includes anactive agent from about 0.0001 percent by weight to about 90 percent byweight of the composition, from about 0.0001 percent by weight to about1 percent by weight, from about 0.0001 percent by weight to about 10percent by weight, from about 0.0001 percent by weight to about 20percent by weight, from about 0.0001 percent by weight to about 30percent by weight, from about 0.0001 percent by weight to about 40percent by weight, from about 0.0001 percent by weight to about 50percent by weight, from about 0.0001 percent by weight to about 60percent by weight, from about 0.0001 percent by weight to about 70percent by weight, from about 0.0001 percent by weight to about 80percent by weight, from about 0.001 percent by weight to about 90percent by weight of the composition, from about 0.001 percent by weightto about 1 percent by weight, from about 0.001 percent by weight toabout 10 percent by weight, from about 0.001 percent by weight to about20 percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the transdermal drug delivery composition includes abioactive agent from about 0.0001 percent by weight to about 90 percentby weight of the composition, from about 0.0001 percent by weight toabout 1 percent by weight, from about 0.0001 percent by weight to about10 percent by weight, from about 0.0001 percent by weight to about 20percent by weight, from about 0.0001 percent by weight to about 30percent by weight, from about 0.0001 percent by weight to about 40percent by weight, from about 0.0001 percent by weight to about 50percent by weight, from about 0.0001 percent by weight to about 60percent by weight, from about 0.0001 percent by weight to about 70percent by weight, from about 0.0001 percent by weight to about 80percent by weight, from about 0.001 percent by weight to about 90percent by weight of the composition, from about 0.001 percent by weightto about 1 percent by weight, from about 0.001 percent by weight toabout 10 percent by weight, from about 0.001 percent by weight to about20 percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the present disclosure includes a transdermal drugdelivery composition including a cell membrane fluidity enhancing agent(e.g., a sterol, wherein exemplary sterols include cholesterol,cholesterol derivatives, phytosterols, or any combination thereof) and apreservative. Examples of preservatives include an anti-microbialpreservative, for example, benzalkonium chloride, thimerosal,chlorhexidine, chlorobutanol, methyl paraben, propyl paraben,phenylethyl alcohol, edetate disodium, sorbic acid, benzoic acid, cetylbromide, cetyl pyridinium chloride, benzyl bromide, EDTA, phenylmercurynitrate, phenylmercury acetate, thimerosal, merthiolate, acetate andphenylmercury borate, polymyxin B sulphate, methyl and propyl parabens,quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodiumproprionate, and sodium perborate, or any combination(s) thereof.

In embodiments the preservatives may be used in any suitable amounts.For example, the preservative may be used in an amount about 0.001% byweight-1.0% by weight based on the total weight of composition.

In embodiments, the transdermal drug delivery composition including acell membrane fluidity enhancing agent (e.g., a sterol, whereinexemplary sterols include cholesterol, cholesterol derivatives,phytosterols, or any combination thereof) has a pH of about 4.5 to about6.5. In other embodiments, the pH is about 5.5.

In some examples, the transdermal drug delivery composition including acell membrane fluidity enhancing agent (e.g., a sterol, whereinexemplary sterols include cholesterol, cholesterol derivatives,phytosterols, or any combination thereof) has an osmolarity of about 200to about 500 mOsm/kg.

The transdermal drug delivery composition should have a zero-rateviscosity that is resistant change over time and/or temperature. Theterms “viscous,” “viscosity”, “zero-rate viscosity’ and the like referherein, in the usual and customary sense, to a measure of the resistanceof a material to deformation (e.g., liquid behavior) upon application ofa force (e.g., shear stress or tensile stress). The viscosity of theemulsions can also depend on the temperature, along with several othereffects, such as shear rate, average droplet size, and droplet sizedistribution. As described herein, the viscosity may typically mean thatthe transdermal drug delivery composition has a zero-rate viscosity ofabout 100 Pa-s to about 1000 kPa-s at 25° C.

In some examples, the transdermal drug delivery composition including acell membrane fluidity enhancing agent (e.g., a sterol, whereinexemplary sterols include cholesterol, cholesterol derivatives,phytosterols, or any combination thereof) has a zero-rate viscosity ofabout 100 Pa-s to about 1000 kPa-s at 25° C.

In some examples, the transdermal drug delivery composition including acell membrane fluidity enhancing agent (e.g., a sterol, whereinexemplary sterols include cholesterol, cholesterol derivatives,phytosterols, or any combination thereof) has rheological propertiesthat have negligible variation with temperature between 25° C. and 37°C.

Transdermal Methods

Also provided herein are methods for providing a transdermal drugdelivery system, the method comprising administering to a subject anyone of the compositions disclosed herein.

In some embodiments, the methods for a transdermal drug delivery systemcomprises treating or preventing conditions including, but not limitedto, pain, diabetes, neurological disorders or diseases, hormonedeficiency, or nausea.

Ophthalmic Compositions

Also provided herein are ophthalmic compositions. The ophthalmiccompositions described herein can be used to treat or prevent ocularsurface disorders, ophthalmic diseases, ophthalmic disorders, and thelike, which include, but are not limited to, dry eyes, styes, epithelialdefects, retinal detachment, conjunctivitis (for example viralconjunctivitis, bacterial conjunctivitis or allergic conjunctivitis),superior limbic keratoconjunctivitis, keratoconjunctivitis sicca,neurotrophic keratopathy, Sjögren's syndrome, ocular cicatricialpemphigoid (OCP), conjunctivitis medicamentosa, corneal ulcerations anderosions, and macular degeneration. Additionally, the ophthalmiccompositions can be used before or after ocular surgery, including forexample, retinal surgery, penetrating keratoplasty and refractivesurgery laser-assisted in situ keratomileusis (LASIK), laser epithelialkeratomileusis (LASEK), or photorefractive keratectomy (PRK).

As used herein the term “ophthalmic composition” refers to a compositionintended for application to the eye or its related or surroundingtissues such as, for example, the eyelid or onto the cornea. The termalso includes compositions intended to therapeutically treat conditionsof the eye itself or the tissues surrounding the eye. The ophthalmiccomposition can be applied topically or by other techniques, known topersons skilled in the art, such as injection to the eye. Examples ofsuitable topical administration to the eye include administration in eyedrops and by spray formulations. A further suitable topicaladministration route is by subconjunctival injection. The compositionscan also be provided to the eye periocularly or retro-orbitally.

In some examples, the disclosed ophthalmic composition can include anactive agent. Exemplary active agents contemplated, include, but are notlimited to, antibiotics, antimicrobials, antivirals, antiseptics, localanesthetics, antihistamines, vasoconstrictors, analgesics,anti-inflammatories, immunosuppressants, immunostimulants,immunomodulators, steroids, and corticosteroids.

In some embodiments, the ophthalmic composition includes one or moreactive agents. For example, the ophthalmic composition includes anvasoconstrictor and an antihistamine, e.g., naphazoline and pheniramine.

In embodiments, the ophthalmic composition includes an active agent fromabout 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the ophthalmic composition includes a bioactive agentfrom about 0.0001 percent by weight to about 90 percent by weight of thecomposition, from about 0.0001 percent by weight to about 1 percent byweight, from about 0.0001 percent by weight to about 10 percent byweight, from about 0.0001 percent by weight to about 20 percent byweight, from about 0.0001 percent by weight to about 30 percent byweight, from about 0.0001 percent by weight to about 40 percent byweight, from about 0.0001 percent by weight to about 50 percent byweight, from about 0.0001 percent by weight to about 60 percent byweight, from about 0.0001 percent by weight to about 70 percent byweight, from about 0.0001 percent by weight to about 80 percent byweight, from about 0.001 percent by weight to about 90 percent by weightof the composition, from about 0.001 percent by weight to about 1percent by weight, from about 0.001 percent by weight to about 10percent by weight, from about 0.001 percent by weight to about 20percent by weight, from about 0.001 percent by weight to about 30percent by weight, from about 0.001 percent by weight to about 40percent by weight, from about 0.001 percent by weight to about 50percent by weight, from about 0.001 percent by weight to about 60percent by weight, from about 0.001 percent by weight to about 70percent by weight, from about 0.001 percent by weight to about 80percent by weight, from about 0.01 percent by weight to about 90 percentby weight, from about 0.01 percent by weight to about 1 percent byweight, from about 0.01 percent by weight to about 10 percent by weight,from about 0.01 percent by weight to about 20 percent by weight, fromabout 0.01 percent by weight to about 30 percent by weight, from about0.01 percent by weight to about 40 percent by weight, from about 0.01percent by weight to about 50 percent by weight, from about 0.01 percentby weight to about 60 percent by weight, from about 0.01 percent byweight to about 70 percent by weight, from about 0.01 percent by weightto about 80 percent by weight, from about 0.1 percent by weight to about90 percent by weight, from about 0.1 percent by weight to about 1percent by weight, from about 0.1 percent by weight to about 10 percentby weight, from about 0.1 percent by weight to about 20 percent byweight, from about 0.1 percent by weight to about 30 percent by weight,from about 0.1 percent by weight to about 40 percent by weight, fromabout 0.1 percent by weight to about 50 percent by weight, from about0.1 percent by weight to about 60 percent by weight, from about 0.1percent by weight to about 70 percent by weight, from about 0.1 percentby weight to about 80 percent by weight of the composition, and anyrange in between.

In embodiments, the present disclosure includes an ophthalmiccomposition including a cell membrane fluidity enhancing agent (e.g., asterol, wherein exemplary sterols include cholesterol, cholesterolderivatives, phytosterols, or any combination thereof) and apreservative. Examples of preservatives include an anti-microbialpreservative, for example, benzalkonium chloride, thimerosal,chlorhexidine, chlorobutanol, methyl paraben, propyl paraben,phenylethyl alcohol, edetate disodium, sorbic acid, benzoic acid, cetylbromide, cetyl pyridinium chloride, benzyl bromide, EDTA, phenylmercurynitrate, phenylmercury acetate, thimerosal, merthiolate, acetate andphenylmercury borate, polymyxin B sulphate, methyl and propyl parabens,quaternary ammonium chloride, sodium benzoate, potassium sorbate, sodiumproprionate, and sodium perborate, or any combination(s) thereof.

In embodiments the preservatives may be used in any suitable amounts.For example, the preservative may be used in an amount about 0.001% byweight-1.0% by weight based on the total weight of composition.

In embodiments, the ophthalmic composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a pH of about 7 to about 7.4 (e.g. neutral pH,or physiological pH). In other embodiments, the pH is about 7.

In some examples, the ophthalmic composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has an osmolarity of about 200 to about 500mOsm/kg.

The ophthalmic composition should have a zero-rate viscosity that isresistant change over time and/or temperature. The terms “viscous,”“viscosity”, “zero-rate viscosity’ and the like refer herein, in theusual and customary sense, to a measure of the resistance of a materialto deformation (e.g., liquid behavior) upon application of a force(e.g., shear stress or tensile stress). The viscosity of the emulsionscan also depend on the temperature, along with several other effects,such as shear rate, average droplet size, and droplet size distribution.As described herein, the viscosity may typically mean that theophthalmic composition has a zero-rate viscosity of about 100 Pa-s toabout 1000 kPa-s at 25° C.

In some examples, the ophthalmic composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has a zero-rate viscosity of about 100 Pa-s toabout 1000 kPa-s at 25° C.

In some examples, the ophthalmic composition including a cell membranefluidity enhancing agent (e.g., a sterol, wherein exemplary sterolsinclude cholesterol, cholesterol derivatives, phytosterols, or anycombination thereof) has rheological properties that have negligiblevariation with temperature between 25° C. and 37° C.

Ophthalmic Methods

Also provided herein are methods for providing ophthalmic symptomrelief, treating underlying pathophysiology or infection, orprophylactically protecting a subject comprising administering to asubject any one of the compositions disclosed herein. In someembodiments, the methods for ophthalmic utility comprises treating orpreventing conditions including, but not limited to ocular surfacedisorders, ophthalmic diseases, ophthalmic disorders, and the like,which include, but are not limited to, dry eyes, styes, epithelialdefects, retinal detachment, conjunctivitis (for example viralconjunctivitis, bacterial conjunctivitis or allergic conjunctivitis),superior limbic keratoconjunctivitis, keratoconjunctivitis sicca,neurotrophic keratopathy, Sjögren's syndrome, ocular cicatricialpemphigoid (OCP), conjunctivitis medicamentosa, corneal ulcerations anderosions, and macular degeneration. Additionally, the ophthalmiccompositions can be used before or after ocular surgery, including forexample, retinal surgery, penetrating keratoplasty and refractivesurgery laser-assisted in situ keratomileusis (LASIK), laser epithelialkeratomileusis (LASEK), or photorefractive keratectomy (PRK). In otherexemplary embodiments, the ophthalmic utility of the disclosedcompositions provides that the compositions can be formulated as asolution, a suspension, a semi-solid, an emulsion, semi-liquid, anointment, a cream, or a controlled-release/sustained-release vehicle.For example, the composition may be in the form of a contact lenssolution, eye drop, eye ointment, and the like.

In embodiments, the method of treating ophthalmic conditions includestreating dry eye associated with or resulting from treating inflammationof the surface of the eye, the lacrimal gland, or the conjunctiva; dryeye associated with any disease process that alters the components ofthe tears; dry eye associated with an increase in the surface of theeye, as in thyroid disease when the eye protrudes forward; and/or dryeye associated with a cosmetic surgery, for example, if the eyelids areopened too widely during surgery.

In embodiments, the method of treating ophthalmic conditions includesameliorating a symptoms, including: stinging or burning of the eye; asandy or gritty feeling as if something is in the eye; episodes ofexcess tears following very dry eye periods; a stringy discharge fromthe eye; pain and redness of the eye; episodes of blurred vision; heavyeyelids; inability to cry when emotionally stressed; uncomfortablecontact lenses; decreased tolerance of reading, working on the computer,or any activity that requires sustained visual attention; and/or eyefatigue.

Additional Applications

The compositions, as described herein can be also formulated for avariety of industrial applications, including but not limited to forproviding lubrication, protection, or moisturization of the surfaces towhich it is applied.

For example, the compositions of the present invention have manyapplications in such areas as auto and motor sports applications;boating applications; farming applications; garage/workshopapplications; hobby and crafts applications; and home and gardenapplications. For example, the composition can be used to provide aprotective coating on metal objects to prevent rust from forming; toprovide lubrication to contacting metal parts; to clean and lubricatemoving parts; to lubricate and penetrate stuck objects; to clean andlubricate tools, saws, and blades; to restore or polish a surface (afterphysicochemical change to the surface). Exemplary surfaces include wood,porcelain, enamel, tile, stainless steel, fiberglass, chrome, andrubber.

Kits

Also provided herein are kits for a composition for symptom relief,treating underlying pathophysiology or infection of the anatomyassociated with the condition, or prophylactically protecting theanatomy in a subject. In embodiments, the kit comprises a stablewater-in-silicone emulsion and a cell membrane fluidity enhancing agent.In other embodiments, the kit also includes an emulsifier, a fatty acid,a preservative, and at least one of, a bioactive agent, a pH bufferingsystem, a viscosity enhancing agent, an antioxidant, a tocopherol, aceramide, or an active agent, and instructions for producing thecomposition. The instructions may describe the steps and reagents forproducing the composition by emulsification. Such steps and reagents maybe in accordance with those that the present application discloses foremulsification.

In embodiments, provided herein are kits for producing a vulvovaginalcomposition for providing vulvovaginal symptom relief, treatingunderlying pathophysiology or infection of the vulvovaginal anatomy, orprophylactically protecting the vulvovaginal anatomy in a subject; thekit comprising, consisting of, or consisting essentially of a stablewater-in-silicone emulsion, an emulsifier, a cell membrane fluidityenhancing agent, a fatty acid, a preservative, and at least one of, abioactive agent, a pH buffering system, a viscosity enhancing agent, anantioxidant, a tocopherol, and an active agent, and instructions forproducing the vulvovaginal composition. The instructions may describethe steps and reagents for producing the vulvovaginal composition byemulsification. Such steps and reagents may be in accordance with thosethat the present application discloses for emulsification.

Also provided herein are dermatological kits comprising the compositionsdescribed herein. The dermatological kits provided herein are fortreating or preventing conditions including, but not limited to eczema,psoriasis, plaque psoriasis, dry skin, chaffed skin, diaper rash, skinrash, hives, poison ivy, skin pain, post-herpetic neuralgia, burns,wound healing, skin infections, dermatitis, atopic dermatitis, acne,impetigo, melanoma, rosacea, chapped skin, chapped lips, or skinwrinkles. In other exemplary embodiments, the dermatological kits of thedisclosed compositions provides that the compositions of the kits can beformulated as cosmetics, skin lotions, skin moisturizers, skin creams,or skin protectants.

In other examples, also provided herein are rectal kits comprising thecompositions described herein. The rectal kits provided herein are fortreating or preventing conditions including, but not limited tohemorrhoids or anal fissures.

In other examples, also provided herein are sunscreen kits comprisingthe compositions described herein. The sunscreen kits provided hereinare for treating or preventing conditions including, but not limited to,UV damage (e.g., sun damage).

In other examples, also provided herein are transdermal drug deliverysystem kits comprising the compositions described herein. Thetransdermal drug delivery system kits provided herein are for treatingor preventing conditions including, but not limited to, pain, diabetes,neurological disorders or diseases, hormone deficiency, or nausea.

In other examples, also provided herein are ophthalmic kits comprisingthe compositions described herein. The ophthalmic kits provided hereinare for treating or preventing conditions, including, but not limitedto, ocular surface disorders, ophthalmic diseases, ophthalmic disorders,and the like.

EXAMPLES

Examples are provided below to facilitate a more complete understandingof the invention. The following examples illustrate the exemplary modesof making and practicing the invention. However, the scope of theinvention is not limited to specific embodiments disclosed in theseExamples, which are for purposes of illustration only, since alternativemethods can be utilized to obtain similar results.

Example 1: Vulvovaginal Cream Produced by Water-in-Silicone (W/O)Emulsification

A W/O emulsified cream is fabricated with a high shear mixing methodutilizing a rotor-stator homogenizer. An aqueous dispersant phasecomprising a lactic acid buffering system (lactic acid/sodium lactate,pH 3.8, 250 mOsm/kg), 0.5% by weight glycogen, 0.1% by weight sodiumascorbate, and 0.1% by weight potassium sorbate, is prepared bydissolving the components in deionized water. A silicone continuousphase comprising 1% by weight Span 80, 2% by weight Tween 80, 1% byweight cholesterol, 0.2% by weight stearic acid, 0.2% by weight oleicacid, 0.2% by weight linoleic acid, 1% by weight tocopheryl acetate, and0.1% by weight benzoic acid, is prepared by dissolving these componentsin dimethicone. The resulting aqueous dispersant phase (250 mL) is addedto the resulting silicone continuous phase (500 mL) under constant highshear mixing using a rotor-stator homogenizer. The resulting stablemicroemulsion is homogenized for 30 minutes to yield a stable,water-in-silicone emulsified cream.

A W/O emulsified cream is fabricated with a high shear mixing methodutilizing a rotor-stator homogenizer. An aqueous dispersant phasecomprising a lactic acid buffering system (lactic acid/sodium lactate,pH 3.8, 250 mOsm/kg), 0.5% by weight glycogen, 0.1% by weight sodiumascorbate, and 0.1% by weight potassium sorbate, is prepared bydissolving the components in deionized water. A silicone continuousphase comprising 2% by weight PEG/PPG-18/18 dimethicone, 1% by weightoctyldodecanol, 1% by weight cholesterol, 0.2% by weight stearic acid,0.2% by weight oleic acid, 0.2% by weight linoleic acid, 1% by weighttocopheryl acetate, and 0.1% by weight benzoic acid, is prepared bydissolving these components in dimethicone. The resulting aqueousdispersant phase (250 mL) is added to the resulting silicone continuousphase (500 mL) under constant high shear mixing using a rotor-statorhomogenizer. The resulting stable microemulsion is homogenized for 30minutes to yield a stable, water-in-silicone emulsified cream.

Example 2: Vulvovaginal Cream with Active Agent Produced byWater-in-Silicone (W/O) Emulsification

Vulvovaginal Cream with 2% Miconazole Produced by Water-in-Silicone(W/O) Emulsification.

A W/O emulsified cream is fabricated with a high shear mixing methodutilizing a rotor-stator homogenizer. An aqueous dispersant phasecomprising a lactic acid buffering system (lactic acid/sodium lactate,pH 3.8, 250 mOsm/kg), 0.5% by weight glycogen, 0.1% by weight sodiumascorbate, and 0.1% by weight potassium sorbate, is prepared bydissolving the components in deionized water. A silicone continuousphase comprising 2% by weight PEG/PPG-18/18 dimethicone, 1% by weightoctyldodecanol, 1% by weight cholesterol, 0.2% by weight stearic acid,0.2% by weight oleic acid, 0.2% by weight linoleic acid, 1% by weighttocopheryl acetate, 0.1% by weight benzoic acid, and 3% by weightmiconazole, is prepared by dissolving these components in dimethicone.The resulting aqueous dispersant phase (250 mL) is added to theresulting silicone continuous phase (500 mL) under constant high shearmixing using a rotor-stator homogenizer. The resulting stablemicroemulsion is homogenized for 30 minutes to yield a stable,water-in-silicone emulsified cream.

Vulvovaginal Cream with 1% Clotrimazole Produced by Water-in-Silicone(W/O) Emulsification.

A W/O emulsified cream is fabricated with a high shear mixing methodutilizing a rotor-stator homogenizer. An aqueous dispersant phasecomprising a lactic acid buffering system (lactic acid/sodium lactate,pH 3.8, 250 mOsm/kg), 0.5% by weight glycogen, 0.1% by weight sodiumascorbate, and 0.1% by weight potassium sorbate, is prepared bydissolving the components in deionized water. A silicone continuousphase comprising 2% by weight PEG/PPG-18/18 dimethicone, 1% by weightoctyldodecanol, 1% by weight cholesterol, 0.2% by weight stearic acid,0.2% by weight oleic acid, 0.2% by weight linoleic acid, 1% by weighttocopheryl acetate, 0.1% by weight benzoic acid, and 1.5% by weightclotrimazole is prepared by dissolving these components in dimethicone.The resulting aqueous dispersant phase (250 mL) is added to theresulting silicone continuous phase (500 mL) under constant high shearmixing using a rotor-stator homogenizer. The resulting stablemicroemulsion is homogenized for 30 minutes to yield a stable,water-in-silicone emulsified cream.

Vulvovaginal Cream with 1% Metronidazole Produced by Water-in-Silicone(W/O) Emulsification.

A W/O emulsified cream is fabricated with a high shear mixing methodutilizing a rotor-stator homogenizer. An aqueous dispersant phasecomprising a lactic acid buffering system (lactic acid/sodium lactate,pH 3.8, 250 mOsm/kg), 0.5% by weight glycogen, 0.1% by weight sodiumascorbate, 0.1% by weight potassium sorbate, and 1.5% by weightmetronidazole, is prepared by dissolving the components in deionizedwater. A silicone continuous phase comprising 2% by weight PEG/PPG-18/18dimethicone, 1% by weight octyldodecanol, 1% by weight cholesterol, 0.2%by weight stearic acid, 0.2% by weight oleic acid, 0.2% by weightlinoleic acid, 1% by weight tocopheryl acetate, 0.1% by weight benzoicacid, is prepared by dissolving these components in dimethicone. Theresulting aqueous dispersant phase (250 mL) is added to the resultingsilicone continuous phase (500 mL) under constant high shear mixingusing a rotor-stator homogenizer. The resulting stable microemulsion ishomogenized for 30 minutes to yield a stable, water-in-siliconeemulsified cream.

Vulvovaginal Cream 4% Nonoxynol-9 Produced by Water-in-Silicone (W/O)Emulsification.

A W/O emulsified cream is fabricated with a high shear mixing methodutilizing a rotor-stator homogenizer. An aqueous dispersant phasecomprising a lactic acid buffering system (lactic acid/sodium lactate,pH 3.8, 250 mOsm/kg), 0.5% by weight glycogen, 0.1% by weight sodiumascorbate, and 0.1% by weight potassium sorbate, is prepared bydissolving the components in deionized water. A silicone continuousphase comprising 2% by weight PEG/PPG-18/18 dimethicone, 1% by weightoctyldodecanol, 1% by weight cholesterol, 0.2% by weight stearic acid,0.2% by weight oleic acid, 0.2% by weight linoleic acid, 1% by weighttocopheryl acetate, 0.1% by weight benzoic acid, and 6% by weightnonoxynol-9, is prepared by dissolving these components in dimethicone.The resulting aqueous dispersant phase (250 mL) is added to theresulting silicone continuous phase (500 mL) under constant high shearmixing using a rotor-stator homogenizer. The resulting stablemicroemulsion is homogenized for 30 minutes to yield a stable,water-in-silicone emulsified cream.

Vulvovaginal Cream with 0.1% Estradiol Produced by Water-in-Silicone(W/O) Emulsification.

A W/O emulsified cream is fabricated with a high shear mixing methodutilizing a rotor-stator homogenizer. An aqueous dispersant phasecomprising a lactic acid buffering system (lactic acid/sodium lactate,pH 3.8, 250 mOsm/kg), 0.5% by weight glycogen, 0.1% by weight sodiumascorbate, and 0.1% by weight potassium sorbate, is prepared bydissolving the components in deionized water. A silicone continuousphase comprising 2% by weight PEG/PPG-18/18 dimethicone, 1% by weightoctyldodecanol, 1% by weight cholesterol, 0.2% by weight stearic acid,0.2% by weight oleic acid, 0.2% by weight linoleic acid, 1% by weighttocopheryl acetate, 0.1% by weight benzoic acid, and 0.15% by weightestradiol, is prepared by dissolving these components in dimethicone.The resulting aqueous dispersant phase (250 mL) is added to theresulting silicone continuous phase (500 mL) under constant high shearmixing using a rotor-stator homogenizer. The resulting stablemicroemulsion is homogenized for 30 minutes to yield a stable,water-in-silicone emulsified cream.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the preferred embodiments of the inventionand that such changes and modifications can be made without departingfrom the spirit of the invention. It is, therefore, intended that theappended claims cover all such equivalent variations as fall within thetrue spirit and scope of the invention.

Example 3: Vulvovaginal Cream Prepared by Water-in-Silicone (W/O)Emulsification Methods

A water-in-silicone emulsified cream was fabricated with a high shearmixing method utilizing a Silverson rotor-stator homogenizer. Briefly,an aqueous dispersant phase comprising 36.4% by weight lactic acidbuffering system (100 mM lactic acid/sodium lactate buffer, pH 3.8, 300mOsm/kg), and 0.1% by weight glycogen, was prepared by dissolving thecomponents in deionized water with mixing at 80° C. (deionized water wascompensated to account for evaporative loss during heating). A siliconecontinuous phase comprising 13% by weight 2-octyldodecanol, 0.25% byweight Span 60, 2% by weight cholesterol, 0.2% by weight stearic acid,and 0.1% tocopheryl acetate was prepared by dissolving these componentsin a mixture of 35.65% by weight dimethicone and 12.3% by weightdimethicone/dimethiconol with mixing at 80° C. The resulting aqueousdispersant phase (80° C.) was added to the resulting silicone continuousphase (80° C.) under constant high shear mixing using a Silversonrotor-stator homogenizer operating at 6500 RPM for 10 minutes. The shearrate of emulsification was then increased to 8000 RPM for 5 minutes toyield a stable, water-in-silicone emulsified cream. The stablemicroemulsion was then transferred to an overhead stirrer to cool byambient equilibration to room temperature and yield a stable, solidifiedwater-in-silicone emulsified cream. All weight percent of constituentsrepresent percent of the total composition.

Rheology: Flow Stress Sweep Protocol

A flow stress sweep protocol was performed on a TA Instruments DiscoveryHR-3 stress controlled rheometer with a 20 mm parallel plate geometryand a 1000 μm gap at 25° C. and 37° C. To execute the protocol, theinstrument parameters were set as follows:

Step 1) Conditioning—Options

-   -   Mode disabled    -   Purge gas only (no active cooling): off mode disabled

Step 2) Flow Sweep

-   -   Temperature 25° C. inherit set point: Off    -   Soak time 60.0 sec wait for temperature: On    -   Logarithmic sweep    -   Stress: 0.1-500 Pa    -   Points per decade: 5    -   Steady-state sensing: On (max equilibration time 60.0 sec)    -   Saple period: 10.0 sec    -   % tolerance: 5.0    -   Consecutive within: 3    -   Scaled time average: Off

Rheology: Oscillatory Frequency and Amplitude Sweep Protocol

An oscillatory frequency and amplitude sweep protocol was performed on aTA Instruments Discovery HR-3 stress controlled rheometer with a 20 mmparallel plate geometry and a 1000 μm gap at 25° C. and 37° C. Toexecute the protocol, the instrument parameters were set as follows:

Step 1) Oscillation—Frequency

-   -   Temperature inherit set point: On    -   Soak time 0.0 sec wait for temperature: Off    -   Strain %: 1%    -   Logarithmic sweep    -   Frequency: 0.1-30 Hz    -   Points per decade: 5

Step 2) Oscillation—Frequency

-   -   Temperature inherit set point: On    -   Soak time 0.0 sec wait for temperature: Off    -   Strain %: 1%    -   Logarithmic sweep    -   Frequency: 30-0.1 Hz    -   Points per decade: 5

Step 3) Oscillation—Amplitude

-   -   Temperature inherit set point: On    -   Angular Frequency: 10 rad/s    -   Logarithmic sweep    -   Strain %: 0.1-100%    -   Points per decade: 10

Rheology: Oscillatory Temperature Sweep Protocol

An oscillatory temperature sweep protocol was performed on a TAInstruments Discovery HR-3 stress controlled rheometer with a 20 mmparallel plate geometry and a 1000 μm gap from 20° C. to 40° C. with astress of 5 Pa and frequency of 10 rad/s. To execute the protocol, theinstrument parameters were set as follows:

Step 1) Conditioning—Sample

-   -   Temperature 20° C. inherit set point: Off    -   Soak time 600.0 sec wait for temperature: On    -   Wait for axial force: Off    -   Perform preshear: Off    -   Perform equilibration: Off

Step 2) Oscillation—Temperature Ramp

-   -   Start temperature: 20° C.    -   Soak time 60.0 sec wait for temperature: On    -   End temperature: 40° C.    -   Soak time after ramp: 0.0 sec    -   Ramp rate: 0.5° C./min    -   Sampling interval: 10 s/pt    -   Stress: 5 Pa    -   Single point    -   Angular frequency: 10 rad/s

Rheology: Results and Discussion

TABLE 1 Water-in-silicone emulsified cream formulation matrix DiM/2-octyl Stable Formulation # DiM DiM-ol dodecanol Chol Span 60 SA TAGlyc LA Emulsion? 1 60.0 — 5.0 2.0 0.5 — — — 32.5 N 2 50.0 10.0 5.0 2.00.5 — — — 32.5 N 3 50.0 10.0 5.0 4.0 0.5 — — — 30.5 N 4 50.0 10.0 5.02.0 1.0 — — — 32.0 N 5 45.0 10.0 10.0 2.0 0.5 — — — 32.5 N 6 40.0 15.010.0 2.0 0.5 — — — 32.5 N 7 40.0 15.0 10.0 2.0 0.25 — — — 32.75 N 8 40.015.0 13.0 2.0 0.25 — — — 29.75 Initially Y 9 35.0 12.5 13.0 2.0 0.25 — —— 36.25 Y 10 35.75 12.3 13.0 2.0 0.25 0.2 — 0.1 36.4 Y 11 35.65 12.313.0 2.0 0.25 0.2 0.1 0.1 36.4 Y 12 12.3 36.65 13.0 2.0 0.25 0.2 0.1 0.136.4 N 13 37.95 10.00 13.00 2.0 0.25 0.2 0.1 0.1 36.4 Y 14 37.95 10.0015.00 0.0 0.25 0.2 0.1 0.1 36.4 N Abbreviations: DiM = Dimethicone,DiM/DiM-ol = Dimethicone/Dimethiconol, Chol = Cholesterol, SA = stearicacid, TA = tocopheryl acetate, Glyc = Glycogen, LA = Lactic acid/Nalactate aqueous buffer

Formulations were generated according to Table 1 and analyzed throughboth macroscopic and microscopic optical imaging to determine stability.Formulation #1 yielded a moderately viscous white cream in the absenceof stable, classical emulsion. Phase separation initiated on day 10 andwas observed to progressively increase. Formulation #2 yielded a higherviscosity white cream in the absence of stable, classical emulsion. Thehigher viscosity was attributed to the incorporation of dimethiconol.Phase separation initiated on day 10 and was observed to progressivelyincrease. Formulation #3 yielded a viscous white cream in the absence ofstable, classical emulsion. Phase separation was initially observed onday 1 indicating the existence of an upper limit to cholesterolincorporation. Formulation #4 failed to yield both a viscous white creamand a stable, classical emulsion. Phase separation was observedimmediately following emulsification indicating the existence of anupper limit to Span 60 incorporation. This phenomenon was likelycorrelated to the concentration of Span 60 being above the criticalmicelle concentration (CMC) of Span 60 in the mixed silicone.Formulation #5 yielded a viscous white cream in the absence of stable,classical emulsion. Phase separation initiated on day 14 and wasobserved to progressively increase. This phenomenon was likelycorrelated to the increased 2-octyldodecanol creating a better interfacewith the Span 60 and cholesterol to better stabilize the water dropletsat the water-silicone interface. Formulation #6 yielded a viscous whitecream in the absence of stable, classical emulsion. Phase separationinitiated on day 4 and was observed to progressively increase. Thisphenomenon indicated that trying to physically confer stability to theemulsion through increasing of the waxy, dimethiconol component isfutile, thus, the emulsion stability is governed predominantly byphysiochemical and thermodynamic parameters. Formulation #7 yielded aviscous white cream in the absence of stable, classical emulsion. Phaseseparation initiated on day 5 and was observed to progressivelyincrease. This phenomenon indicated the utility of decreasing the Span60 concentration. Formulation #8 yielded a viscous white cream in thepresence of an emulsion more consistent with a stable, classicalemulsion (FIG. 3A-3C). Weeping of the silicone phase was observed on day6, though the emulsion was observed to maintain moderate stableintegrity. Phase separation initiated on day 15 and was observed toprogressively increase. This phenomenon further supports the hypothesisthat a specific balance of the emulsifiers in essential to conferringemulsion stability. Further, the weeping of the oil phase indicated thatthe ratio of water to silicone should be altered to incorporate moreaqueous dispersant phase. Formulation #9 yielded a viscous white creamin the presence of a stable, classical emulsion (FIG. 4A-4C). This creamhas shown no signs of phase separation or instability, confirming theimportance of the water to silicone ratio for emulsion stability.Formulation #10 (FIG. 5A-5C) and Formulation #11 also yielded a viscouswhite cream in the presence of a stable, classical emulsion. Thesecreams have shown no signs of phase separation or instability.Formulation #12 yielded a viscous white cream in the absence of stable,classical emulsion. This phenomenon demonstrated the importance ofcontrolling the silicone phase constituents. Formulation #13 alsoyielded a viscous white cream in the presence of a stable, classicalemulsion. Removal of cholesterol from Formulation #13 to createFormulation #14, yielded complete phase separation and a lack ofemulsion formation (FIG. 6A-6E). This phenomenon demonstrated theimportance of cholesterol as an emulsifier and interfacial stabilizer.

The mechanical properties of select formulations were examined byrheometry and the results are summarized in Table 2 below.

TABLE 2 Comparison of the rheological properties with predicatevulvovaginal creams Zero Rate Viscosity Amplitude Sweep Amplitude Sweep(kPa-s) Frequency Sweep Comparison (Crossover) Comparison (Strain)Formulation 25° C. 37° C. Comparison 25° C. 37° C. 25° C. 37° C.Monistat 7 45 95 Some widening  1800 Pa  1.9 Pa 0.5% 1.3% Vagisil 329142 Some widening 386.8 Pa 326.2 Pa 29.2% 30.4%  #9 95 105 No widening323.6 Pa 435.6 Pa 10.4% 11.3% #10 346.4 198.6 No widening 336.1 Pa 248.3Pa 12.1% 11.9% #11 166.8 261.1 No widening 288.2 Pa 374.8 Pa 7.45% 8.56%#13 315.8 143.2 No widening 384.2 Pa 292.3 Pa 12.4% 12.5%

Utilizing a flow stress sweep protocol, zero rate viscosities of 95kPa-s and 105 kPa-s were determined at 25° C. and 37° C., respectively,for formulation #9 (FIG. 7A-7D). An oscillatory frequency sweep showed amostly parallel relationship between the storage modulus (G′) and theloss modulus (G″) with some convergence at high frequency (FIG. 8A-8B).Further, no widening or hysteresis was observed across the frequencydomain and the difference between G′ and G″ at 25° C. and 37° C. wasobserved to be negligible. An oscillatory amplitude sweep showed only asmall difference between the crossover points of G′ and G″ and strainsat 25° C. and 37° C., thus indicating the transition from solid-like toliquid-like is similar across the defined temperature range (FIG.9A-9B). An oscillatory temperature sweep revealed a slight negativeslope for G′, G″, and complex viscosity (FIG. 10). Further, thisprovided another piece of evidence in support of the negligibledifferences in Formulation #9 at 25° C. and 37° C. Taken in aggregate,these rheological properties demonstrate ideal properties for avulvovaginal cream designed to be stored at room temperature and appliedto anatomy at body temperature. These ideal properties were alsoobserved in Formulation #11.

Comparison of Mechanical Properties and Osmolarities: Formulation #9 vs.Predicate Creams for Vaginal Application

A comparison of the mechanical properties and osmolarities forFormulation #9 and predicate creams (e.g., Monistat 7, Vagisil, and 2%Clotrimazole) for vaginal application was performed, and the results aredepicted in Table 3 below.

TABLE 3 Comparison of Mechanical Properties and Osmolarities Zero-RateFrequency Sweep Osmolarity Formulation Viscosity Comparison AmplitudeSweep Comparison (mOsm/kg) Monistat 7  45 kPa-s @ 25 C. Some widening 25C. Crossover @ ~1800 Pa ND  95 kPa-s @ 37 C. 25 C. Strain @ ~0.5% 37 C.Crossover @ ~1.9 Pa 37 C. Strain @ 1.3% Vagisil 329 kPa-s @ 25 C. Somewidening 25 C. Crossover @ 386.8 1374  142 kPa-s @ 37 C. 25 C. Strain @29.2% 37 C. Crossover @ 326.2 Pa 37 C. Strain @ 30.4% Clotrimazole 590kPa-s @ 25 C. Some widening 25 C. Crossover @ 2552.4 Pa 125 281 kPa-s @37 C. 25 C. Strain @ 29% 37 C. Crossover @ 1703.3 Pa 37 C. Strain @ 5.4%#9  95 kPa-s @ 25 C. No widening 25 C. Crossover @ 323.6 Pa 300 105kPa-s @ 37 C. 25 C. Strain @ 10.4% 37 C. Crossover @ 435.6 Pa 37 C.Strain @ 11.3%

Other Embodiments

While the invention has been described in conjunction with the detaileddescription thereof, the foregoing description is intended to illustrateand not limit the scope of the invention, which is defined by the scopeof the appended claims. Other aspects, advantages, and modifications arewithin the scope of the following claims.

The patent and scientific literature referred to herein establishes theknowledge that is available to those with skill in the art. All UnitedStates patents and published or unpublished United States patentapplications cited herein are incorporated by reference. All publishedforeign patents and patent applications cited herein are herebyincorporated by reference. Genbank and NCBI submissions indicated byaccession number cited herein are hereby incorporated by reference. Allother published references, documents, manuscripts and scientificliterature cited herein are hereby incorporated by reference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the claims.

Additional Exemplary Embodiments Include

In an embodiment, provided herein is a dermatological compositioncomprising a stable water-in-silicone emulsion having a continuoussilicone phase and an aqueous phase, wherein the emulsion comprises asterol at a concentration from about 0.1% to about 4% by weight, of thetotal weight of the composition. In embodiments, the sterol comprisescholesterol, or cholesterol derivatives.

In an embodiment, provided herein are methods for preventing or treatinga dermatological condition in a subject, the method comprisingadministering to the subject a composition comprising a stablewater-in-silicone emulsion, wherein the emulsion has a sterol at aconcentration from about 0.1% to about 4% by weight of the total weightof the composition.

In an embodiment, provided herein is a rectal composition comprising astable water-in-silicone emulsion having a continuous silicone phase andan aqueous phase, wherein the emulsion comprises a sterol at aconcentration from about 0.1% to about 4% by weight, of the total weightof the composition. In embodiments, the sterol comprises cholesterol, orcholesterol derivatives.

In an embodiment, provided herein are methods for treating a rectalcondition in a subject, the method comprising administering to thesubject a composition comprising a stable water-in-silicone emulsion,wherein the emulsion has a sterol at a concentration from about 0.1% toabout 4% by weight of the total weight of the composition.

In an embodiment, provided herein is a sunscreen composition comprisinga stable water-in-silicone emulsion having a continuous silicone phaseand an aqueous phase, wherein the emulsion comprises a sterol at aconcentration from about 0.1% to about 4% by weight, of the total weightof the composition. In embodiments, the sterol comprises cholesterol, orcholesterol derivatives.

In an embodiment, provided herein are methods for preventingUV-radiation damage in a subject, the method comprising administering tothe subject a composition comprising a stable water-in-siliconeemulsion, wherein the emulsion has a sterol at a concentration fromabout 0.1% to about 4% by weight of the total weight of the composition.

In an embodiment, provided herein is a transdermal drug deliverycomposition comprising a stable water-in-silicone emulsion having acontinuous silicone phase and an aqueous phase, wherein the emulsioncomprises a sterol at a concentration from about 0.1% to about 4% byweight, of the total weight of the composition. In embodiments, thesterol comprises cholesterol, or cholesterol derivatives.

In an embodiment, provided herein are methods for treating pain,diabetes, neurological disorders or diseases, hormone deficiency, ornausea in a subject, the method comprising administering to the subjecta composition comprising a stable water-in-silicone emulsion, whereinthe emulsion has a sterol at a concentration from about 0.1% to about 4%by weight of the total weight of the composition.

In an embodiment, provided herein is an ophthalmic compositioncomprising a stable water-in-silicone emulsion having a continuoussilicone phase and an aqueous phase, wherein the emulsion comprises asterol at a concentration from about 0.1% to about 4% by weight, of thetotal weight of the composition. In embodiments, the sterol comprisescholesterol, or cholesterol derivatives.

In an embodiment, provided herein are methods for preventing or treatingan ophthalmic condition in a subject, the method comprisingadministering to the subject a composition comprising a stablewater-in-silicone emulsion, wherein the emulsion has a sterol at aconcentration from about 0.1% to about 4% by weight of the total weightof the composition.

1. A composition comprising a stable water-in-silicone emulsion having acontinuous silicone phase and an aqueous phase, wherein the emulsioncomprises a non-silicone emulsifier comprising cholesterol or acholesterol derivative at a concentration from about 0.1% to about 4% byweight of the total weight of the composition and a sorbitan ester.2-29. (canceled)
 30. A method for treating or preventing a condition ina subject, comprising: applying to a tissue surface a compositioncomprising a stable water-in-silicone emulsion having a continuoussilicone phase and an aqueous phase, wherein the emulsion comprises anon-silicone emulsifier comprising cholesterol or a cholesterolderivative at a concentration from about 0.1% to about 4% by weight ofthe total weight of the composition and a sorbitan ester, and whereinthe composition is used in an amount effective to treat said condition.31. The method of claim 30, wherein the tissue surface comprises anepithelial surface or a mucosal surface.
 32. The method of claim 30,wherein the condition comprises a vaginal condition or a rectalcondition.
 33. The method of claim 32, wherein the vaginal conditioncomprises a decrease in estrogen concentration, atrophic vaginitis,vulvar and vaginal atrophy, bacterial vaginosis, vaginal dryness,vaginal itch, vaginal irritation, dyspareunia, bacterial infection,yeast infection, urinary tract infection, menopause, peri-menopause,post-menopause, a sexually transmitted infection, sexually transmitteddisease, or combinations thereof.
 34. The method of claim 32, whereinthe rectal condition comprises hemorrhoids, anal fissures, a rash, orcombinations thereof.
 35. The method of claim 30, wherein thecomposition is administered to the tissue surface via topicaladministration, vaginal administration, rectal administration, mucosaladministration, or transdermal administration.
 36. The method of claim30, wherein the composition is formulated as a personal lubricant, as amoisturizer, as an ointment, as a lotion, as a topical cream, as a skinprotectant, or for drug delivery.
 37. The method of claim 33, whereinthe composition further comprises one or more active agents.
 38. Themethod of claim 37, wherein the one or more active agents comprise anantifungal agent, an antibiotics, a spermicide, estrogen, an estrogenderivative, progesterone, a progesterone derivative, an estrogenprecursor, a steroid, an anti-inflammatory agent, an antiviral agent, anantiretroviral agent, a non-nucleoside reverse transcriptase inhibitor,a protease inhibitor, fusion inhibitors, an integrase inhibitor, apost-attachment inhibitor, or combinations thereof.
 39. The method ofclaim 33, wherein the composition further comprises glycogen.
 40. Themethod of claim 33, wherein the composition has a pH of about 3 to about5.
 41. The method of claim 34, wherein the composition further comprisesone or more active agents.
 42. The method of claim 41, wherein the oneor more active agents comprise a vasoconstrictor, an anti-inflammatoryagent, a steroid, a local anesthetic, an alpha-adrenergic receptoragonist, onabotulinumtoxin A, a calcium channel inhibitor, a nitrate, orcombinations thereof
 43. The method of claim 34, wherein the compositionhas a pH of about 7 to about
 8. 44. The method of claim 30, wherein thecomposition has an osmolarity of about 200 to about 500 mOsm/kg.